Salts, crystal forms, and production methods thereof

ABSTRACT

Provided are salts of (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine and various of crystal forms thereof, and compositions, medicaments, pharmaceutically acceptable formulations thereof, and methods of making same. In addition, provided are compounds comprising specific particle size distributions of crystalline (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine HCl and methods of making and modulating the particle size distributions.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.16/277,443, filed Feb. 15, 2019. U.S. Ser. No. 16/277,443 claimedpriority to U.S. Provisional Application No. 62/710,416, filed Feb. 16,2018, the contents of both of which are incorporated by reference hereinin their entirety.

FIELD

Provided herein are(S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine saltsand polymorphic forms of thereof, formulations comprising them, methodsof making them, and methods for their use for the treatment of variousdiseases and disorders. Provided herein are pharmaceutical compositionscomprising(S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanaminehydrochloride and polymorphic forms of thereof, methods of making thecompositions, and methods for their use for the treatment of variousdiseases and disorders.

BACKGROUND

(S)-(4,5-Dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine isdescribed in U.S. Pat. No. 8,710,245 (the '245 patent). It has thefollowing chemical structure:

Uses of (S)-(4,5-Dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanaminein the treatment, prevention, or management of affective disorders andother various CNS disorders are also disclosed in the '245 patent.

Drug substances are most frequently administered orally by means ofsolid dosage forms such as tablets and capsules. Tablets remain popularas a dosage form because of the advantages afforded both to themanufacturer (e.g., simplicity and economy of preparation, stability andconvenience in packaging, shipping and dispensing) and to the subject(e.g., accuracy of dosage, compactness, portability, blandness of tasteand ease of administration). The preparation of tablets almostuniversally requires that the active pharmaceutical ingredient (API) bea solid. In the manufacture of solid APIs, it is necessary to obtainproducts with reproducible properties, including chemical purity andcomposition. For crystalline solid APIs that exhibit polymorphism, it isimportant to produce the desired polymorph to assure the bioavailabilityand stability of the drug substance. In addition to considerations ofpolymorphism, the manufacture of tablets is often sensitive to crystalsize and morphology. While the target of many crystallization operationsis to produce crystals large enough to be isolated easily on standardfiltration equipment, smaller particle sizes are often desired toenhance the dissolution rate, improve bioavailability, and facilitatetablet formation. A reliable, reproducible process for preparingshelf-stable, readily bioavailable, pharmaceutical dosage forms for(S)-(4,5-Dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine wouldbe highly desirable.

SUMMARY

The present disclosure provides salts of(S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine,formulations or compositions comprising these salts, method of preparingthe compound, salts, formulations or compositions thereof, as well aspolymorphs of the salts. In various aspects, the present inventionsrelate to substantially pure crystalline forms of(S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanaminehydrochloride, methods of producing same, compositions, medicaments andformulations including same, and methods of treating various diseasesand disorders using same.

In various aspects, provided are crystalline forms of(S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanaminehydrochloride, ((S)-TPMA HCl). In various embodiments, provided arecrystalline forms of(S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanaminehydrochloride of crystalline Form A. In various embodiments, crystalline(S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanaminehydrochloride of Form A is characterized by a powder x-ray diffractionpattern comprising peaks, in terms of 2-theta, at 9.6±0.2°, 14.9±0.2°,20.5±0.2°, and 25.1±0.2°, in various embodiments further comprisingpeaks at 20.2±0.2° and 20.8±0.2°, and in various embodiments furthercomprising peaks at 20.2±0.2° and 20.8±0.2° and a prominent peak at twoor more of 17.9±0.2°, 24.8±0.2° and 27.1±0.2°.

In various embodiments, the present inventions provide substantiallyenantiomerically pure crystalline forms of (S)-TPMA HCl of Form A. Forexample, in various embodiments, the present inventions providecrystalline forms of TPMA HCl that contain greater than about 90%(S)-TPMA HCl and less than about 10% of (R)-TPMA HCl, greater than about95% (S)-TPMA HCl and less than about 5% of (R)-TPMA HCl, greater thanabout 97% (S)-TPMA HCl and less than about 3% of (R)-TPMA HCl, greaterthan about 99% (S)-TPMA HCl and less than about 1% of (R)-TPMA HCl,greater than about 99.5% (S)-TPMA HCl and less than about 0.5% of(R)-TPMA HCl, greater than about 99.7% (S)-TPMA HCl and less than about0.3% of (R)-TPMA HCl, or greater than about 99.9% (S)-TPMA HCl and lessthan about 0.1% of (R)-TPMA HCl.

In various embodiments, the present inventions provide substantiallychemically pure crystalline forms of (S)-TPMA HCl of Form A. Forexample, in various embodiments, the present inventions providecrystalline (S)-TPMA HCl of Form A that has a greater than about 80%chemical purity, greater than about 90% chemical purity, greater thanabout 95% chemical purity, greater than about 97% chemical purity,greater than about 99% chemical purity, greater than about 99.5%chemical purity, greater than about 99.7% chemical purity, or greaterthan about 99.9% chemical purity. In various embodiments, provided iscrystalline (S)-TPMA HCl of Form A that has less than about 8000 ppmresidual solvents, less than about 6000 ppm residual solvents, less thanabout 4000 ppm residual solvents, less than about 2000 ppm residualsolvents, less than about 1000 ppm residual solvents, less than about800 ppm residual solvents, or less than about 500 ppm residual solvents.Parts per million (ppm) are based on the weight of solvent as aproportion of the weight of compound plus solvent, as is commonlyunderstood. (See USP 40, section <467>.)

In various aspects, provided are methods for preparing(S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanaminehydrochloride as crystalline Form A.

In various embodiments, the method comprises:

(a) dissolving(S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine freebase in a solvent system comprising an alkyl alcohol of 4 carbons orless;

(b) adding excess HCl in an alkyl alcohol of 4 carbons or less; and

(c) isolating crystalline(S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanaminehydrochloride. In various embodiments, the alkyl alcohol is one or moreof n-propanol, isopropanol, and n-butanol, and in various embodiments,the alkyl alcohol is preferably isopropanol.

In various embodiments of methods for preparing(S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanaminehydrochloride as Form A, the method comprises:

(a) combiningracemic-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanaminewith a stoichiometric excess of (R)-mandelic acid in a solvent;

(b) isolating(S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamineR-mandelate salt;

(c) freeing(S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine fromthe (R)-mandelate salt;

(d) dissolving the(S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine in asolvent system comprising an alkyl alcohol of 4 carbons or less;

(e) adding HCl in an alkyl alcohol of 4 carbons or less;

(f) isolating crystalline(S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanaminehydrochloride. In various embodiments, the alkyl alcohol is one or moreof n-propanol, isopropanol, and n-butanol, and in various embodiments,the alkyl alcohol is preferably isopropanol.

In various aspects, provided are solid oral dosage forms comprising atablet core and an optional coating. The tablet core comprising: fromabout 30 mg to about 120 mg of crystalline(S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanaminehydrochloride of Form A; and one or more of: (a) one or more fillers,such as, e.g., mannitol, and microcrystalline cellulose, and the like;(b) a disintegrant; and (c) a lubricant. In various embodiments, theoptional tablet coating comprises one or more of (a) a polymer coatingsystem; and (b) a polishing agent, such as, e.g., carnauba wax.

In various aspects, the present disclosure relates to methods oftreating neurological diseases or disorders with a composition,formulation and/or medicament comprising (S)-TPMA, salts, and polymorphsthereof. In various aspects, the present inventions relate to methods oftreating neurological diseases or disorders with a composition,formulation and/or medicament comprising crystalline (S)-TPMA HCl. Invarious preferred embodiments, the crystalline (S)-TPMA HCl comprisescrystalline (S)-TPMA HCl of Form A. The neurological diseases anddisorders include, but are not limited to: schizophrenia spectrumdisorder, schizophrenia negative symptoms, prodromal schizophrenia,delusional disorder, psychosis, attenuated psychosis syndrome,Parkinson's disease psychosis, psychotic disorder, delirium, Tourette'ssyndrome, post-traumatic stress disorder, behavior disorder, affectivedisorder, depression, bipolar depression, major depressive disorder,dysthymia, bipolar disorder, manic disorder, seasonal affectivedisorder, obsessive-compulsive disorder, narcolepsy, REM behaviordisorder, substance abuse or dependency, Lesch-Nyhan disease, Wilson'sdisease, autism, Alzheimer's disease with agitation and/or psychosis,and Huntington's chorea.

These and other objects, features, and advantages of the presentinventions will become apparent from the following detailed descriptionof the various aspects and embodiments of the inventions taken inconjunction with the accompanying tables and drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

In the accompanying drawings like reference numerals indicate likeelements and features in the various figures. For clarity, not everyelement may be labeled in every figure. In addition, the drawings arenot necessarily complete when viewed without reference to the text,emphasis instead being placed upon illustrating the principles of theinventions.

The following abbreviations are used herein. The abbreviation DSC refersto differential scanning calorimetry; the abbreviation XRD refers tox-ray diffraction; the abbreviation XRPD refers to x-ray powderdiffraction; the abbreviation NMR refers to nuclear magnetic resonance;the abbreviation DVS refers to dynamic vapor sorption; the abbreviationFBRM refers to focused beam reflectance measurement; the abbreviationHPLC refers to high performance liquid chromatography; and theabbreviation GC refers to gas chromatography; the abbreviation PSDrefers to particle size distribution; the abbreviations D4,3 and D(4,3)refer to the volume mean diameter of a volume percent PSD; theabbreviation D50 refers to the median of a distribution where half thepopulation resides above this value and half resides below; theabbreviation D10 refers to the point on a distribution where 10% of thepopulation resides below this value; the abbreviation D90 refers to thepoint on a distribution where 90% of the population resides below thisvalue; the abbreviation PVM refers to particle vision and measurement;the abbreviation TPMA refers to(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine. Otherabbreviations not explicitly described herein have their normal meaningsin the art.

FIG. 1A, FIG. 1B, FIG. 1C and FIG. 1D present SEM images of crystalline(S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanaminehydrochloride; polymorph Form A (FIG. 1A and FIG. 1B) and polymorph FormB (FIG. 1C and FIG. 1D).

FIG. 2A and FIG. 2B present XRPD patterns for(S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanaminehydrochloride of Form A; FIG. 2A is the XRPD measured in transmissionmode and FIG. 2B in reflection mode.

FIG. 2C presents an XRPD pattern for(S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanaminehydrochloride of Form B.

FIG. 3A is a DSC thermogram for(S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanaminehydrochloride, of polymorph Form A.

FIG. 3B and FIG. 3C are DSC thermograms for(S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanaminehydrochloride, of polymorph Form B.

FIG. 4A, FIG. 4B, FIG. 4C, FIG. 4D, and FIG. 4E present various types ofRaman spectra of for(S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanaminehydrochloride of polymorph Form A and polymorph Form B; where FIG. 4Apresents Raman spectra of Form A; where FIG. 4B presents Raman spectraof Form B; where FIG. 4C presents Raman spectra of both Form A (lowertrace) and Form B (upper trace); FIG. 4D presents a Terahertz (THz)Raman spectra of Form A peak at 1089 cm⁻¹ (wavenumbers); and FIG. 4Epresents a Terahertz (THz) Raman spectra of Form B peak at 1162 cm⁻¹(wavenumbers).

FIG. 5 is a DVS water sorption isotherm for(S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanaminehydrochloride, of polymorph Form A.

FIG. 6A and FIG. 6B present various HCl dosing profiles data of Example2 for (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanaminehydrochloride, of polymorph Form A.

FIG. 7A and FIG. 7B present various PSD (particle size distribution)data of Example 2 for(S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanaminehydrochloride, of polymorph Form A.

FIG. 8A, FIG. 8B, and FIG. 8C present various PSD (particle sizedistribution) data of Example 2 for(S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanaminehydrochloride, of polymorph Form A.

FIG. 9A presents various PSD (particle size distribution) data ofExample 2 for(S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanaminehydrochloride, of polymorph Form A.

FIG. 9B and FIG. 9C present SEM images of crystalline(S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanaminehydrochloride, of polymorph Form A.

FIG. 10 is a ¹H NMR spectrum of(S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanaminehydrochloride, of polymorph Form A.

FIG. 11 presents an XRPD pattern for(S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamineR-mandelate.

FIG. 12 is a DSC thermogram for(S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamineR-mandelate.

FIG. 13 is a DVS isotherm for(S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamineR-mandelate.

FIG. 14 presents an XRPD pattern for(S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamineL-tartrate.

FIG. 15 is a DSC thermogram for(S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamineL-tartrate.

FIG. 16 is a DVS isotherm for(S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamineL-tartrate.

FIG. 17 presents an XRPD pattern for(S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamineD-tartrate Form DA.

FIG. 18 presents an XRPD pattern for(S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamineD-tartrate Form DB.

FIG. 19 presents an XRPD pattern for(S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamineD-tartrate Form DC.

FIG. 20 is a DSC thermogram for(S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamineD-tartrate Form DA.

FIG. 21 is a DSC thermogram for(S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamineD-tartrate Form DB.

FIG. 22 is a DSC thermogram for(S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamineD-tartrate Form DC.

FIG. 23 is a DVS isotherm for(S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamineD-tartrate DA.

FIG. 24 is a DVS isotherm for(S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanaminemesylate.

FIG. 25 presents an XRPD pattern for(S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanaminebesylate Form BA.

FIG. 26 is a DSC thermogram for(S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanaminebesylate Form BA.

FIG. 27 is a DVS isotherm for(S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanaminebesylate Form BA.

FIG. 28 is an XRPD of(S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanaminebesylate Form BA showing the indexing results.

FIG. 29 is schematic diagram showing the controlled sub-surface additionof the acid stream at the region of a high mixing zone near the impellertip.

FIG. 30 is a dosing profile of HCl IPA solution (mL) over time (minute).

FIG. 31 is a graph of the particle side distribution for the dosingprofiles, volume (%) over particle size (um).

FIG. 32 presents an XRPD pattern for(S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine freebase.

DETAILED DESCRIPTION

All published documents cited herein are hereby incorporated herein byreference in their entirety.

Reference in the specification to “one embodiment,” “an embodiment,”“one aspect,” or “an aspect” means that a particular, feature, structureor characteristic described in connection with the embodiment or aspectis included in at least one embodiment or aspect of the teachings. Asused herein, the singular forms “a”, “an” and “the” are intended toinclude the plural forms as well, unless the context clearly indicatesotherwise.

Unless otherwise specified, the word “includes” (or any variationthereon, e.g., “include”, “including”, etc.) is intended to beopen-ended. For example, “A includes 1, 2 and 3” means that A includesbut is not limited to 1, 2 and 3.

As used herein, the term “subject,” to which administration iscontemplated includes, but is not limited to, humans (i.e., a male orfemale of any age group, e.g., a pediatric subject (e.g., infant, child,adolescent) or adult subject (e.g., young adult, middle-aged adult orsenior adult)) and/or other primates (e.g., cynomolgus monkeys, rhesusmonkeys); mammals, including commercially relevant mammals such ascattle, pigs, horses, sheep, goats, cats, and/or dogs; and/or birds,including commercially relevant birds such as chickens, ducks, geese,quail, and/or turkeys. In some embodiments, the term “subject” refers topatient, such as a human patient.

As used herein, the terms “treatment,” “treat,” and “treating” refer toreversing, alleviating, delaying the onset of, or inhibiting theprogress of a disease or disorder, or one or more symptoms thereof,including but not limited to therapeutic benefit. In variousembodiments, treatment may be administered after one or more symptomshave developed. In other embodiments, treatment may be administered inthe absence of symptoms. For example, treatment may be administered to asubject prior to the onset of symptoms (e.g., in light of a history ofsymptoms and/or in light of genetic or other susceptibility factors).Treatment may also be continued after symptoms have resolved, forexample to prevent or delay their recurrence.

Therapeutic benefit includes eradication and/or amelioration of theunderlying disorder being treated; it also includes the eradicationand/or amelioration of one or more of the symptoms associated with theunderlying disorder such that an improvement is observed in the subject,notwithstanding that the subject may still be afflicted with theunderlying disorder. In some embodiments, “treatment” or “treating”includes one or more of the following: (a) inhibiting the disorder (forexample, decreasing one or more symptoms resulting from the disorder,and/or diminishing the extent of the disorder); (b) slowing or arrestingthe development of one or more symptoms associated with the disorder(for example, stabilizing the disorder and/or delaying the worsening orprogression of the disorder); and/or (c) relieving the disorder (forexample, causing the regression of clinical symptoms, ameliorating thedisorder, delaying the progression of the disorder, and/or increasingquality of life.)

As used herein, the term “therapeutically effective amount” or“effective amount” refers to an amount that is effective to elicit thedesired biological or medical response, including the amount of acompound that, when administered to a subject for treating a disorder,is sufficient to effect such treatment of the disorder. The effectiveamount will vary depending on the compound, the disorder, and itsseverity, and the age, weight, etc. of the subject to be treated. Theeffective amount may be in one or more doses (for example, a single doseor multiple doses may be required to achieve the desired treatmentendpoint). An effective amount may be considered to be given in aneffective amount if, in conjunction with one or more other agents, adesirable or beneficial result may be or is achieved. Suitable doses ofany co-administered compounds may optionally be lowered due to thecombined action, additive or synergistic, of the compound.

As used herein, “delaying” development of a disorder mean to defer,hinder, slow, stabilize, and/or postpone development of the disorder.Delay can be of varying lengths of time, depending on the history of thedisease and/or the individual being treated.

As used herein, “prevention” or “preventing” refers to a regimen thatprotects against the onset of the disorder such that the clinicalsymptoms of the disorder do not develop. Accordingly, “prevention”relates to administration of a therapy, including administration of acompound disclosed herein, to a subject before signs of the diseases aredetectable in the subject (for example, administration of a compounddisclosed herein to a subject in the absence of a detectable syndrome ofthe disorder). The subject may be an individual at risk or developingthe disorder.

As used herein, an “at risk” individual is an individual who is at riskof developing a disorder to be treated. This may be shown, for example,by one or more risk factors, which are measurable parameters thatcorrelate with development of a disorder and are known in the art.

Compositions of the present inventions may be administered orally,parenterally, by inhalation, topically, rectally, nasally, buccally,sublingually, vaginally or via an implanted reservoir. The term“parenteral” as used herein includes subcutaneous, intravenous,intramuscular, intra-articular, intra-synovial, intrasternal,intrathecal, intrahepatic, intralesional and intracranial injection orinfusion techniques. Preferably, the compositions are administeredorally, intraperitoneally or intravenously. Sterile injectable forms ofthe compositions of the present inventions may be aqueous or oleaginoussuspension. These suspensions may be formulated according to techniquesknown in the art using suitable dispersing or wetting agents andsuspending agents. The sterile injectable preparation may also be asterile injectable solution or suspension in a non-toxic parenterallyacceptable diluent or solvent, such as, for example, as a solution in1,3-butanediol. Acceptable vehicles and solvents that may be employed,include, but are not limited to, water, Ringer's solution and isotonicsodium chloride solution. In addition, sterile, fixed oils areconventionally employed as a solvent or suspending medium.Pharmaceutically acceptable compositions of this invention may be orallyadministered in any orally acceptable dosage form including capsules,tablets, aqueous suspensions or solutions.

Polymorphism is the ability of an element or compound to crystallizeinto distinct crystalline phases. Although the term polymorph impliesmore than one morphology, the term is still used in the art, and herein,to refer to a crystalline structure of a compound as a polymorph evenwhen only one crystalline phase is currently known. Thus, polymorphs aredistinct solids sharing the same molecular formula as other polymorphsand the amorphous (non-crystalline) phase, however since the propertiesof any solid depend on its structure, polymorphs often exhibit physicalproperties distinct from each other and the amorphous phase, such asdifferent solubility profiles, different melting points, differentdissolution profiles, different thermal stability, differentphotostability, different hygroscopic properties, different shelf life,different suspension properties and different physiological absorptionrates. Inclusion of a solvent in the crystalline solid leads tosolvates, and in the case of water as a solvent, hydrates, often leadsto a distinct crystalline form with one or more physical properties thatare distinctly different from the non-solvated and non-hydrated (e.g.,anhydrous) crystalline form.

As used herein, the term “polymorph” refers to different crystalstructures achieved by a particular chemical entity. As used herein, theterm “solvate” refers to a crystal form where a stoichiometric ornon-stoichiometric amount of solvent, or mixture of solvents, isincorporated into the crystal structure. Similarly, the term “hydrate”refers to a crystal form where a stoichiometric or non-stoichiometricamount of water is incorporated into the crystal structure.

As used herein the term “span,” when referring to a PSD is evaluated asfollows: Span=[(D90−D10)/D50], for D values of a PSD distribution basedon volume.

As used herein, the term “prominent peak,” in the context of an XRPD,means a peak with a greater than about 15% relative intensity. As usedherein, the term “insignificant peak,” in the context of an XRPD, meansa peak with a less than about 2% relative intensity.

As used herein the term “polymorph purity” refers to the weight % thatis the specified polymorph form. For example, when a crystalline(S)-TPMA HCl of Form A is characterized as having greater than 95%polymorph purity, that means that greater than 95% by weight of thesubstance is crystalline (S)-TPMA HCl of Form A and less than 5% byweight of any other polymorph (e.g., Form B) or amorphous form of(S)-TPMA HCl.

As used herein the terms “chiral purity” and “enantiomeric purity” areused interchangeably and refers to the weight % that is the specifiedenantiomer. For example, when a (S)-TPMA containing substance (such as acompound or crystal) is characterized as having greater than 90% chiralpurity, that means that greater than 95% by weight of the TPMA in thesubstance is the (S)-TPMA enantiomer and less than 5% by weight is inany other enantiomeric form of TPMA.

As used herein the term “chemical purity” refers to the weight % that isthe specified chemical entity, including specified enantiomeric orpolymorph form. For example, when a crystalline (S)-TPMA HCl of Form Ais characterized as having greater than 95% chemical purity, that meansthat greater than 95% by weight of the substance is (S)-TPMA HCl of FormA and less than 5% by weight of any other compound including otherenantiomers and polymorphs.

“Pharmaceutically acceptable” or “physiologically acceptable” refer tocompounds, salts, compositions, dosage forms and other materials whichare useful in preparing a pharmaceutical composition that is suitablefor veterinary or human pharmaceutical use.

As used herein, the term “pharmaceutically acceptable salt” refers tothose salts which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response and the like, andare commensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well known in the art. For example, S. M. Berge etal., describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 1977, 66, 1-19. Pharmaceutically acceptablesalts of the compounds of this invention include those derived fromsuitable inorganic and organic acids and bases. Examples ofpharmaceutically acceptable, nontoxic acid addition salts are salts ofan amino group formed with inorganic acids such as hydrochloric acid,hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid orwith organic acids such as acetic acid, oxalic acid, maleic acid,tartaric acid, citric acid, succinic acid or malonic acid or by usingother methods used in the art such as ion exchange. Otherpharmaceutically acceptable salts include adipate, alginate, ascorbate,aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate,camphorate, camphorsulfonate, citrate, cyclopentanepropionate,digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate,glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate,hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate,lactate, laurate, lauryl sulfate, malate, maleate, malonate,methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate,oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate,phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate,thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and thelike. Although pharmaceutically acceptable counter ions will bepreferred for preparing pharmaceutical formulations, other anions arequite acceptable as synthetic intermediates. Thus X may bepharmaceutically undesirable anions, such as iodide, oxalate,trifluoromethanesulfonate and the like, when such salts are chemicalintermediates.

As used herein, the term “pharmaceutically acceptable excipient”includes, without limitation, any binder, filler, adjuvant, carrier,excipient, glidant, sweetening agent, diluent, preservative,dye/colorant, flavor enhancer, surfactant, wetting agent, dispersingagent, suspending agent, stabilizer, isotonic agent, solvent,emulsifier, anti-caking agent, flavor, desiccants, plasticizers,disintegrants, lubricant, polymer matrix system, and polishing agents,that have been approved by the United States Food and DrugAdministration as being acceptable for use in humans or domesticanimals.

It is to be understood that in various embodiments, the pharmaceuticalcompositions of the present inventions comprise one or morepharmaceutically acceptable excipients, including, but not limited to,one or more binders, bulking agents, buffers, stabilizing agents,surfactants, wetting agents, lubricating agents, diluents,disintegrants, viscosity enhancing or reducing agents, emulsifiers,suspending agents, preservatives, antioxidants, opacifying agents,glidants, processing aids, colorants, sweeteners, taste-masking agents,perfuming agents, flavoring agents, polishing agents, polymer matrixsystems, plasticizers and other known additives to provide an elegantpresentation of the drug or aid in the manufacturing of a medicament orpharmaceutical product comprising a composition of the presentinventions. Examples of carriers and excipients well known to thoseskilled in the art and are described in detail in, e.g., Ansel, HowardC., et al., Ansel's Pharmaceutical Dosage Forms and Drug DeliverySystems. Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro,Alfonso R., et al. Remington: The Science and Practice of Pharmacy.Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe, Raymond C.Handbook of Pharmaceutical Excipients. Chicago, Pharmaceutical Press,2005.

In various embodiments, non-limiting examples of excipients include, butare not limited to, corn starch, potato starch, or other starches,gelatin, natural and synthetic gums such as acacia, sodium alginate,alginic acid, other alginates, powdered tragacanth, guar gum, celluloseand its derivatives (e.g., ethyl cellulose, cellulose acetate,carboxymethyl cellulose calcium, sodium carboxymethyl cellulose),polyvinyl pyrrolidone, methyl cellulose, pre-gelatinized starch,hydroxypropyl methyl cellulose, (e.g., Nos. 2208, 2906, 2910),hydroxypropyl cellulose, titanium dioxide, talc, calcium carbonate(e.g., granules or powder), microcrystalline cellulose, powderedcellulose, dextrates, kaolin, silicic acid, sorbitol, starch,pre-gelatinized starch, agar-agar, alginic acid, calcium carbonate,microcrystalline cellulose, croscarmellose sodium, crospovidone,polacrilin potassium, sodium starch glycolate, potato or tapioca starch,other starches, pre-gelatinized starch, other starches, clays, otheralgins, other celluloses, gums, calcium stearate, magnesium stearate,mineral oil, light mineral oil, glycerin, sorbitol, mannitol,polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate,talc, hydrogenated vegetable oil (e.g., peanut oil, cottonseed oil,sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zincstearate, ethyl oleate, ethyl laureate, agar, a syloid silica gel(AEROSIL200 (fumed silica, manufactured by Evonik), a coagulated aerosolof synthetic silica (marketed by Evonik Degussa), CAB-O-SIL (a pyrogenicsilicon dioxide product sold by Cabot Co. of Boston, Mass.), colorantsand mixtures thereof.

In various embodiments, the compositions are formulated with one or morepharmaceutically acceptable excipients in accordance with known andestablished practice. In various embodiments, the compositions describedherein are referred to as formulation or medicament. Thus, in variousembodiments the composition are formulated as, for example, a liquid,powder, elixir, injectable solution, or suspension. Formulations fororal use are preferred and may be provided, for instance, as tablets,caplets, or capsules, wherein the pharmacologically active ingredientsare mixed with an inert solid diluent. In various embodiments, thecompositions described herein are formulated as a tablet. In variousembodiments, the oral dosage form is a solid oral dosage form. Invarious embodiments, the solid oral dosage form comprises a tablet, andin various embodiments the solid oral dosage form comprises a capsule.Tablets may also include granulating and disintegrating agents, and maybe coated or uncoated. Formulations for topical use may be provided, forexample as topical solutions, lotions, creams, ointments, gels, foams,patches, powders, solids, sponges, tapes, vapors, pastes or tinctures.

Accordingly, in various aspects and embodiments provided herein aremethods for preparing a particular salt of a specific enantiomer in acrystalline polymorph form that lends itself to pharmaceutical dosageforms. In addition, in various aspects and embodiments provided areformulations for salt polymorph for a unique dosage form that exhibitsadvantageous properties as a medicament.

Provided herein is compound(S)-(−)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine,having the following structure:

(S)-(−)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine isnamed or identified using other commonly recognized nomenclaturesystems. For example, the compound may be named or identified withcommon names, systematic names, or non-systematic names. Thenomenclature systems that are commonly recognized in the art ofchemistry include, but are not limited to, Chemical Abstract Service(CAS) and International Union of Pure and Applied Chemistry (IUPAC). TheIUPAC name provided by ChemDraw Professional 15.0 has been used hereinfor Compound 1.

(S)-(−)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanaminereferred to herein for the sake of brevity as (S)-TPMA. In someembodiments, (S)-TPMA may be prepared as a pharmaceutically acceptablesalt. Non-limiting examples of pharmaceutically acceptable salts includehydrochlorides, malates, tartrates, citrates, phosphates, sulfates,pyrosulfates, bisulfates, sulfites, bisulfites, monohydrogen-phosphates,dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides,bromides, iodides, acetates, propionates, decanoates, caprylates,acrylates, formates, isobutyrates, caproates, heptanoates, propiolates,oxalates, malonates, succinates, suberates, sebacates, fumarates,maleates, butyne-1,4-dioates, hexyne-1,6-dioates, benzoates,chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates,methoxybenzoates, phthalates, sulfonates, methylsulfonates,propylsulfonates, besylates, tosylates, xylenesulfonates,naphthalene-1-sulfonates, naphthalene-2-sulfonates, phenylacetates,phenylpropionates, phenylbutyrates, lactates, gamma-hydroxybutyrates,glycolates, and mandelates. Lists of other suitable pharmaceuticallyacceptable salts are found in Remington: The Science and Practice ofPharmacy, 21st Edition, Lippincott Williams and Wilkins, Philadelphia,Pa., 2006.

In some embodiments, provided herein is(S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanaminehydrochloride,(S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanaminebesylate,(S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamineR-mandelate,(S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamineL-tartrate,(S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamineD-tartrate,(S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanaminemesylate, and(S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamineL-malate.

The present inventors have found that the(S)-(−)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanaminehydrochloride anhydrate, henceforth referred to as(S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanaminehydrochloride, also referred to herein for the sake of brevity as(S)-TPMA HCl,

has desirable solubility under physiologic conditions, is chemicallystable and a crystalline solid physically well-suited to formulation.

The present inventors have also found that (S)-TPMA HCl exists in twopolymorphic forms, polymorph Form A and polymorph Form B. In addition,Form A was found to be thermodynamically stable, not substantiallyconverting to other polymorphs or amorphous form. Formation of Form Bwas found to be kinetically favored over Form A. Form B was, however,found to be less thermodynamically stable than Form A; Form B beingtransformed to Form A when Form B is held as a slurry and slightlyheated.

Crystal forms of (S)-TPMA and (S)-TPMA HCl and crystalline forms ofother salts, hydrates and solvates, including those of the presentinventions, may be characterized and differentiated using a number ofconventional analytical techniques, including but not limited to X-raypowder diffraction (XRPD) patterns, nuclear magnetic resonance (NMR)spectra, Raman spectra, Infrared (IR) absorption spectra, dynamic vaporsorption (DVS), Differential Scanning calorimetry (DSC), and meltingpoint. Chemical purity may be characterized using a number ofconventional analytical techniques, including but not limited to highperformance liquid chromatography (HPLC) and gas chromatography (GC).Chiral purity (also known as enantiomeric purity) may be characterizedusing a number of conventional analytical techniques, including but notlimited to high performance liquid chromatography (HPLC).

In various embodiments, the crystal forms of (S)-TPMA HCl arecharacterized by X-ray powder diffraction (XRPD). XRPD is a technique ofcharacterizing a powdered sample of a material by measuring thediffraction of X-rays by the material. The result of an XRPD experimentis a diffraction pattern. Each crystalline solid produces a distinctivediffraction pattern containing sharp peaks as a function of thescattering angle 2θ (2-theta). Both the positions (corresponding tolattice spacing) and the relative intensity of the peaks in adiffraction pattern are indicative of a particular phase and material.This provides a “fingerprint” for comparison to other materials. Incontrast to a crystalline pattern comprising a series of sharp peaks,amorphous materials (liquids, glasses etc.) produce a broad backgroundsignal in a diffraction pattern.

It is to be understood that the apparatus employed, humidity,temperature, orientation of the powder crystals, and other parametersinvolved in obtaining an XRPD pattern may cause some variability in theappearance, intensities, and positions of the lines in the diffractionpattern. An XRPD pattern that is “substantially in accord with” that ofa FIG. provided herein (e.g., FIG. 2A) is an XRPD pattern that would beconsidered by one skilled in the art to represent a compound possessingthe same crystal form as the compound that provided the XRPD pattern ofthat FIG. That is, the XRPD pattern may be identical to that of theFIG., or more likely it may be somewhat different. Such an XRPD patternmay not necessarily show each of the lines of the diffraction patternspresented herein, and/or may show a slight change in appearance,intensity, or a shift in position of said lines resulting fromdifferences in the conditions involved in obtaining the data. A personskilled in the art is capable of determining if a sample of acrystalline compound has the same form as, or a different form from, aform disclosed herein by comparison of their XRPD patterns.

For example, one skilled in the art could use HPLC to determine theenantiomeric identity of an(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanaminehydrochloride (TPMA HCl) sample and if, for example, the sample isidentified as (S)-TPMA HCl, one skilled in the art can overlay an XRPDpattern of the sample with FIG. 2A and/or FIG. 2B, and using expertiseand knowledge in the art, readily determine whether the XRPD pattern ofthe sample is substantially in accordance with the XRPD pattern ofcrystalline (S)-TPMA HCl of Form A presented in FIG. 2A or (S)-TPMA HClof Form B presented in FIG. 2B, or neither. If, for example, HPLCidentifies the sample as being (S)-TPMA HCl and the sample XRPD patternis substantially in accord with FIG. 2A, the sample can be readily andaccurately identified as (S)-TPMA HCl of Form A.

In various embodiments, the crystal forms of (S)-TPMA HCl arecharacterized by Raman Spectroscopy and THz Raman Spectroscopy. Thepositions and the relative intensity of the peaks are indicative of thevibrational, and other low frequency modes, of a compound and canprovides a “fingerprint” for comparison to other compounds. THz Ramanspectroscopy provides further “fingerprint” information by extending therange into the terahertz frequency region of both Stokes and anti-Stokessignals, and THz Raman spectroscopy in general providing greaterstructural information, such as distinguishing between polymorphs, thanRaman spectroscopy.

In various embodiments, the crystal forms of (S)-TPMA HCl arecharacterized by melting point. Melting points were determined byconventional methods such as capillary tube and may exhibit a range overwhich complete melting occurs, or in the case of a single number, a meltpoint of that temperature ±1° C.

In various embodiments, the crystal forms of (S)-TPMA HCl arecharacterized by differential scanning calorimetry (DSC). DSC is athermoanalytical technique in which the difference in the amount of heatrequired to increase the temperature of a sample and a reference ismeasured as a function of temperature. Both the sample and reference aremaintained at substantially the same temperature throughout theexperiment. The result of a DSC experiment is a curve of heat flowversus temperature, called a DSC thermogram.

In various embodiments, the hygroscopicity of crystal forms of (S)-TPMAHCl are characterized by dynamic vapor sorption (DVS). DVS is agravimetric technique that measures how much of a solvent is adsorbed bya sample by varying the vapor concentration surrounding the sample(e.g., relative humidity) and measuring the change in mass. In thepresent application, DVS is used to generate water sorption isotherms,which represent the equilibrium amount of vapor sorbed as a function ofsteady state relative vapor pressure at a constant temperature.

As used herein, the term “substantially non-hygroscopic” refers to acompound exhibiting less than a 1% maximum mass change in water sorptionisotherms, at 25° C. scanned over 0 to 90% relative humidity, asmeasured by dynamic vapor sorption (DVS).

In various aspects and embodiments, the present inventions relate to newcrystalline forms of (S)-TPMA HCl, Form A and Form B. Form A has beenfound to be a distinct polymorph from Form B, having a distinctlydifferent structure and XRPD pattern, as well as different THz Ramanspectra.

FIGS. 1A and 1B present SEM images of (S)-TPMA HCl Form A crystals andFIGS. 1C and 1D SEM images of (S)-TPMA HCl Form B crystals. Form A wasobserved to form plate crystals and was determined by XRPD to have amonoclinic crystal system, while the Form B was observed to form hollowneedle crystals and was determined by XRPD to have an orthorhombiccrystal system. As isolated from conventional synthesis or saltconversion, (S)-TPMA hydrochloride typically appears as a mixture ofForms A and B.

Form B was determined to be less thermodynamically stable than Form A,and can be converted by solid state conversion to Form A. The solidstate conversion of the polymorph Form B needles to polymorph Form Ablocks can be monitored by X-ray diffraction, and it was discoveredunexpectedly that the visible morphology retains the needle shape whilethe crystal lattice changes to that of Form A.

The XRPD pattern of FIG. 2A was obtained in transmission mode with aStoe Stadi P (G.52.SYS.S072) with a Mythen1K detector, using Cu Kαradiation; with measurements in transmission mode; 40 kV and 40 mA tubepower; a curved Ge monochromator detector; 0.02° 20 step size, with a 12s step time, and a 1.5-50.5° 20 scanning range. The detector mode wasset to: step scan with 1° 20 detector step and sample preparation was a10 to 20 mg sample placed between two acetate foils and clamped in aStoe transmission sample holder. Samples were rotated during themeasurement.

The XRPD patterns of FIGS. 2B and 2C were obtained with a Bruker 08Advance, Cu Kα radiation (λ=1.54180 Å), with measurements in reflectionmode; 40 kV/40 mA tube power; LynxEye detector, 0.02° step size in 20,using 37 s per step, and a 2.5°-50° 20 scanning range. The sample wasprepared on silicon single crystal sample holders with 1.0 mm depth andwas covered with Kapton foil. The sample was rotated during themeasurement.

Further details of the crystal data and crystallographic data collectionparameters are summarized in Table 1, and a listing of the peaks of theXRPD of FIG. 2A are listed in Table 2A, the peaks of the XRPD of FIG. 2Bare listed in Table 2B, and the peaks of the XRPD of FIG. 2C are listedin Table 2C.

TABLE 1 (S)-TPMA hydrochloride Form A and Form B Single Crystal Data andCollection Parameters Form A, blocks Form B, needles Empirical formulaC₉H₁₄NOSCl C₉H₁₄NOSCl Molecular formula [C₉H₁₄NOS]⁺[Cl]⁻[C₉H₁₄NOS]⁺[Cl]⁻ Formula weight 219.72 219.72 Temperature 100(2) K100(2) K Wavelength 1.54184 Å 1.54184 Å Crystal system MonoclinicOrthorhombic Space group P21 (#4) P212121 (#19) Unit cell dimensions a =9.1719(2) Å; a = 5.10405(5) Å; α = 90°. α = 90°. b = 11.2183(3) Å; b =10.2114(1) Å; β = 92.146(2)°. β = 90°. c = 10.2092(2) Å; c = 20.5496(2)Å; γ = 90°. γ = 90°. Volume 1049.72(4) Å{circumflex over ( )}31071.035(18) Å{circumflex over ( )}3 Z 4 4 Density (calculated) 1.390Mg/m³ 1.363 Mg/m³ Absorption coefficient 4.765 mm⁻¹ 4.670 mm⁻¹ F(000)464 464 Crystal size 0.0823 × 0.0529 × 0.0396 0.3254 × 0.0539 × 0.0366mm³ mm³ Theta range for data collection 4.33 to 76.58°. 4.30 to 76.77°.Index ranges −11 <= h <= 10, −13 <= k <= −6 <= h <= 6, −12 <= k <= 14,−12 <= l <= 12 12, −25 <= l <= 25 Reflections collected 11895 22468Independent reflections 4211 [R(int) = 0.0362] 2261 [R(int) = 0.0532]Completeness to θ = 76.58° 99.50% 100.00% Absorption correctionAnalytical Analytical Max. and min. transmission 0.860 and 0.776 0.864and 0.435 Refinement method Full-matrix least-squares on Full-matrixleast-squares on F2 F2 Data/restraints/parameters 4211/1/237 2261/3/136Goodness-of-fit on F2 1.041 1.085 Final R indices [I > 2σ (I)] R1 =0.0264, wR2 = 0.0587 R1 = 0.0270, wR2 = 0.0665 R indices (all data) R1 =0.0289, wR2 = 0.0601 R1 = 0.0291, wR2 = 0.0680 Absolute structureparameter −0.001(10) −0.032(18) Largest diff. peak and hole 0.260 and−0.188 e.Å⁻³ 0.329 and −0.573 e.Å⁻³

In some embodiments, provided herein is crystalline(S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanaminehydrochloride characterized by monoclinic space group P21. In someembodiments, the crystalline(S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanaminehydrochloride has unit cell dimensions: a is about 9.2 Å, b is about11.2 Å, c is about 10.2 Å, α is about 90°, β is about 92°, and γ isabout 90°.

In some embodiments, provided herein is crystalline(S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanaminehydrochloride characterized by orthorhombic space group P212121. In someembodiments, the crystalline(S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanaminehydrochloride has unit cell dimensions: a is about 5.1 Å, b is about10.2 Å, c is about 20.5 Å, α is about 90°, β is about 90°, and γ isabout 90°.

TABLE 2A (S)-TPMA hydrochloride Form A XRPD (FIG. 2A) Peak List 2-ThetaRelative Height 9.55 22.61 11.63 3.1 12.35 11.47 12.65 8.6 14.89 20.715.27 9.77 15.67 5.44 17.91 24.67 18.38 12.71 19.00 28.32 19.16 25.9219.49 4.49 20.19 27.17 20.48 33.87 20.72 15.32 24.84 19.16 25.11 10025.57 76.5 26.11 3.05 26.56 2.56 26.86 6.74 27.07 16.04 27.24 4.78 27.522.28 28.60 2.32 28.91 5.9 29.22 2.58 29.98 2.52 30.55 3.87 30.81 6.6431.63 23.29 32.00 2.86 32.84 4.04 33.05 5.83 34.37 1.81 34.98 2.25 35.412.97 36.61 1.82 37.02 3.83 37.59 1.99 38.46 1.71 39.47 4.25

TABLE 2B (S)-TPMA hydrochloride Form A XRPD (FIG. 2B) Peak List 2-ThetaRelative Height 9.59 27.73 11.70 3.44 12.35 17.88 12.69 11.1 13.12 3.5214.93 22.25 15.31 11.24 15.71 4.04 17.28 7.28 17.95 18.38 18.41 14.0319.16 91.74 19.53 9.85 20.23 31.95 20.51 42.51 20.76 27.67 21.60 3.4122.25 3.33 22.77 3.87 24.82 77.41 25.14 100 25.59 82 26.13 7.25 26.586.46 27.10 19.49 27.55 6.3 28.87 27.5 29.24 5.41 29.99 8.48 30.55 8.7430.83 12.69 31.63 24.78 32.02 5.46 33.03 12.75 34.31 5.42 34.93 9.1235.45 5.72 35.99 4.93 36.68 6.56 37.58 8.48 38.49 4.42 39.47 6.41

TABLE 2C (S)-TPMA hydrochloride Form B XRPD (FIG. 2C) Peak List 2-ThetaRelative Height 8.54 9.1 8.89 0.3 11.76 0.8 12.12 21.6 12.45 0.2 15.461.8 17.12 100 17.48 1.7 17.82 2.6 18.32 0.5 19.18 14.2 21.56 0.5 23.169.5 24.80 0.9 25.80 6.6 26.20 0.2 27.26 2.1 27.62 0.6 29.06 1.2 31.5015.4 31.81 0.4 32.42 0.5 33.87 0.6 34.68 1 35.00 1.9 35.76 1.6 36.94 0.937.24 0.4 39.28 0.1 40.00 0.7 40.20 1.1 43.08 5.8 43.74 2 44.60 0.6

Raman and THz Raman Spectra

The Raman and THz Raman spectroscopic analysis was performed using aKaiser Raman RXN-Hybrid-785 system with laser wavelength 785 nm, with aspectral coverage of +100 cm⁻¹ to +1875 cm⁻¹ for the Raman spectra and aspectral coverage of −200 cm⁻¹ to +200 cm⁻¹ for the Tz Raman spectra;spectral resolution was 4 cm⁻¹. The Raman spectra of FIGS. 4A, 4B and 4Cwere collected with the regular immerse Raman probe, and the THz Ramanspectra of FIGS. 4D and 4E were collected with the THz-Raman® Probe.

Referring to FIGS. 4A and 4C, the Form A crystals of (S)-TPMA HCl wereused as a powder and the spectra taken in a dark chamber. Referring toFIGS. 4B and 4C, the Form B crystals of (S)-TPMA HCl were freshlygenerated by dissolving Form A crystals in isopropanol and then rotaryevaporating off the solvent, then the Form B crystals were used as apowder and the spectra taken in a dark chamber. A listing of variouspeaks in the spectra of FIG. 4A are listed in Table 3A, and variouspeaks in the spectra of FIG. 4B are listed in Table 3B.

Referring to FIG. 4D, the Form A crystals of (S)-TPMA HCl were suspendedin isopropanol at room temperature and the THz-Raman® Probe used to takethe spectra in the suspension. Referring to FIG. 4E, the Form B crystalsof (S)-TPMA HCl were generated by the reverse dumping addition offreebase (S)-TPMA to the HCl solution, and THz-Raman® Probe immediatelyused to take the spectra in suspension.

Both the Raman spectra and THz Raman spectra were obtained using: (a)cosmic ray filtering’ and (b) baseline correction and smoothing toobtain interpretable data when necessary; and for the THz Raman spectrabackground subtraction of a well filled with IPA collected with the sameconditions.

TABLE 3A (S)-TPMA hydrochloride Form A Raman Spectra (FIG. 4A) Peak ListRaman shift, cm⁻¹ Relative Peak Height 378.9 31.53 417.6 100.00 430.236.77 448.8 35.97 576.9 44.40 620.7 31.18 750.0 66.84 1001.1 48.841030.8 35.65 1080.9 48.59 1439.1 37.41 1602.3 41.81

TABLE 3B (S)-TPMA hydrochloride Form B Raman Spectra (FIG. 4B) Peak ListRaman shift, cm⁻¹ Relative Peak Height 378.9 33.95 417.6 100.00 429.639.79 448.8 38.43 577.2 48.47 620.4 33.63 750.3 68.58 1001.1 49.141030.8 37.64 1080.6 50.10 1445.1 44.63

Referring to FIGS. 4D and 4E, the THz Raman spectra of the twopolymorphs is distinctly different. For example, in various embodiments,the THZ Raman spectra of the Raman peak of Form B at 1162 cm⁻¹ and theTHZ Raman spectra of the Raman peak of Form A at 1089 cm⁻¹ can be usedto distinguish these polymorphs.

Crystalline (S)-TPMA HCl of Forms A and B exhibit different propertiesand different “fingerprints”. Various measurements presented herein onthese polymorphs are summarized in Table 4.

TABLE 4 Form A Form B SEM Image FIG. 1A, FIG. 1B FIG. 1C, FIG. 1D XRPDPattern FIG. 2A. FIG. 2B FIG. 2C DSC Thermograph FIG. 3A FIGS. 3B-3CRaman FIG. 4A FIG. 4B THz Raman FIG. 4D FIG. 4E

In various embodiments, the present inventions provide a crystallineform of (S)-TPMA HCl characterized by an XRPD pattern comprising peaks,in terms of 2-theta, at 9.6±0.2°, 14.9±0.2°, 20.5±0.2°, and 25.1±0.2°,and a DSC thermogram having a peak at 214±2° C.

In various embodiments, the present inventions provide a crystallineform of (S)-TPMA HCl characterized by an XRPD pattern comprising peaks,in terms of 2-theta, at 9.6±0.2°, 14.9±0.2°, 20.5±0.2°, and 25.1±0.2°,and a differential scanning calorimetry thermogram substantially inaccord with FIG. 3A.

In various embodiments, the present inventions provide a crystallineform of (S)-TPMA HCl characterized by an XRPD pattern comprising peaks,in terms of 2-theta, at 9.6±0.2°, 14.9±0.2°, 20.5±0.2°, and 25.1±0.2°,and a Raman spectra substantially in accord with FIG. 4A and/or a THzRaman spectra substantially in accord with FIG. 4D.

In various embodiments, the present inventions provide a crystallineform of (S)-TPMA HCl characterized by an XRPD pattern comprising peaks,in terms of 2-theta, at 8.6±0.2°, 17.2±0.2°, and 25.9±0.2°, and a DSCthermogram having a peak at 215±2° C.

In various embodiments, the present inventions provide a crystallineform of (S)-TPMA HCl characterized by an XRPD pattern comprising peaks,in terms of 2-theta, at 8.6±0.2°, 17.2±0.2°, and 25.9±0.2°, and adifferential scanning calorimetry thermogram substantially in accordwith FIG. 3B or FIG. 3C.

In various embodiments, the present inventions provide a crystallineform of (S)-TPMA HCl characterized by an XRPD pattern comprising peaks,in terms of 2-theta, at 8.6±0.2°, 17.2±0.2°, and 25.9±0.2°, and a Ramanspectra substantially in accord with FIG. 4B and/or a THz Raman spectrasubstantially in accord with FIG. 4E.

In various embodiments, the present inventions provide a crystallineform of (S)-TPMA HCl that is the substantially non-hygroscopic. Invarious embodiments, the present inventions provide a crystalline(S)-TPMA HCl of Form A that has a maximum mass change of less than about1%, less than about 0.5%, less than about 0.3%, less than about 0.2%, orless than about 0.1% in water sorption isotherms as measured by dynamicvapor sorption (DVS), at 25° C. scanned over 0 to 90% relative humidity.

FIG. 5 and Table 5 present DVS water sorption isotherms for crystalline(S)-TPMA HCl of Form A. The water sorption isotherms were generatedusing a VTI SGA-100 dynamic vapor sorption analyzer. Samples were driedpre-analysis at 25° C. with equilibrium criteria of 0.0000 wt % changesin 5 minutes or a maximum of 180 minutes. Isotherm equilibrium criteriawere the lesser of 0.01 wt % change in 5 minutes or 180 minutes at eachrelative humidity (RH) step. Temperature was fixed at 25° C. and therelative humidity steps (5% to 95% to 5%) were in 5% increments. Initialsample size ranged from 41 to 47 mg.

FIG. 5 presents DVS water sorption for two different lots of crystalline(S)-TPMA HCl of Form A, and Table 5 lists the data plotted in FIG. 5. Ascan be seen, crystalline (S)-TPMA HCl Form A is substantiallynon-hygroscopic, exhibiting a maximum mass change of only 0.2% at 95%relative humidity (RH), and less than a 0.1% mass change at 90% RH andbelow.

TABLE 5 (S)-TPMA HCl Form A DVS Water Sorption Isotherms of FIG. 5 Lot 1Lot 2 (upright (square symbols) triangle symbols) Relative Change ElapseChange Elapse Humidity Mass Time Mass Time (%) (%) (min) (%) (min) 10.000 155.6 0.000 41.6 5 −0.002 329.5 0.001 52.2 10 −0.002 416.5 0.00161.2 15 −0.001 425.0 0.001 69.7 20 −0.001 434.5 0.001 81.7 25 0.000454.0 0.001 93.7 30 0.001 466.0 0.001 105.2 35 0.001 479.5 0.002 118.240 0.002 491.0 0.002 129.7 45 0.003 500.6 0.003 139.2 50 0.003 511.60.003 150.2 55 0.004 520.6 0.003 159.2 60 0.005 531.6 0.004 170.2 650.006 542.6 0.005 181.2 70 0.007 553.6 0.005 192.2 75 0.008 562.6 0.006201.2 80 0.010 571.6 0.008 210.2 85 0.014 580.6 0.011 219.2 90 0.021589.6 0.017 228.2 95 0.088 616.0 0.117 260.2

In various embodiments, the present inventions provide a crystallineform of (S)-TPMA HCl characterized by an XRPD pattern comprising peaks,in terms of 2-theta, at 9.6±0.2°, 14.9±0.2°, 20.5±0.2°, and 25.1±0.2°;in various embodiments, further characterized by peaks at 20.2±0.2° and20.8±0.2°; and in various embodiments, further characterized by two ormore prominent peaks in its XRPD pattern selected from those at17.9±0.2°, 24.8±0.2° and 27.1±0.2°, in terms of 2-theta. In variousembodiments, the present inventions provide a crystalline form of(S)-TPMA HCl characterized by an XRPD pattern substantially in accordwith FIG. 2B.

In various embodiments, the present inventions provide a crystallineform of (S)-TPMA HCl of Form A characterized by the followingproperties, an XRPD pattern comprising peaks, in terms of 2-theta, at9.6±0.2°, 14.9±0.2°, 20.5±0.2°, and 25.1±0.2°, a melting point of 214±2°C., a chiral purity of greater than about 99%, a chemical purity greaterthan about 99%, a residual solvent content of less than about 8000 ppm,and is substantially non-hygroscopic.

In various embodiments, the present inventions provide a crystallineform of (S)-TPMA HCl characterized by the following properties, an XRPDpattern comprising peaks, in terms of 2-theta, at 9.6±0.2°, 14.9±0.2°,20.5±0.2°, and 25.1±0.2° and one or more of the following:

-   -   (a) the powder x-ray diffraction pattern further comprising        peaks, in terms of 2-theta, at 20.2±0.2° and 20.8±0.2°;    -   (b) the powder x-ray diffraction pattern further comprising a        prominent peak, in terms of 2-theta, at two of more of        17.9±0.2°, 24.8±0.2° and 27.1±0.2°;    -   (c) a melting point of 214±2° C.;    -   (d) a differential scanning calorimetry thermogram comprising a        peak at 214±2° C.;    -   (e) a differential scanning calorimetry thermogram substantially        in accord with FIG. 3A;    -   (f) a Raman spectra substantially in accord with FIG. 4A, a THz        Raman spectra substantially in accord with FIG. 4D, or both;    -   (g) a chiral purity of greater than about: (i) 90%, (ii)        95%, (iii) 97%, (iv) 99%, (v) 99.5%, (vi) 99.7%, or (vii) 99.9%;    -   (h) a chemical purity of greater than about: (i) 80%, (ii)        90%, (iii) 95%, (iv) 97%, (v) 99%, (vi) 99.5%, (vii) 99.7%,        or (viii) 99.9%;    -   (i) residual solvents present in an amount less than about: (i)        8000 ppm, (ii) 6000 ppm, (iii) 4000 ppm, (iv) 2000 ppm, (v) 1000        ppm, (vi) 800 ppm, or 500 ppm;    -   (j) as measured by dynamic vapor sorption (DVS), at 25° C.        scanned over 0 to 95% relative humidity, a maximum mass change        in water sorption isotherms of less than about (i) 2%, (ii)        1%, (iii) 0.5%, (iv) 0.4%, (v) 0.3%, (vi) 0.2%, or (vii) 0.1%;        and    -   (k) as measured by dynamic vapor sorption (DVS), at 25° C.        scanned over 0 to 90% relative humidity, a maximum mass change        in water sorption isotherms of less than about (i) 1%, (ii)        0.5%, (iii) 0.4%, (iv) 0.3%, (v) 0.2%, or (vi) 0.1%; and        preferably less than about 0.2%.

In various embodiments, the present inventions provide a crystallineform of (S)-TPMA HCl characterized by an XRPD pattern comprising peaks,in terms of 2-theta, at 8.6±0.2°, 17.2±0.2°, and 25.9±0.2°; and invarious embodiments, further characterized by peaks in its XRPD patternselected at, 23.2±0.2°, and 31.5±0.2°, in terms of 2-theta. In variousembodiments, the present inventions provide a crystalline form of(S)-TPMA HCl characterized by an XRPD pattern substantially in accordwith FIG. 2C.

In various embodiments, the present inventions provide a crystallineform of (S)-TPMA HCl of Form B characterized by the followingproperties, an XRPD pattern comprising peaks, in terms of 2-theta, at8.6±0.2°, 17.2±0.2°, and 25.9±0.2°, and a melting point of 215±2° C.

In various embodiments, the present inventions provide a crystallineform of (S)-TPMA HCl characterized by the following properties, an XRPDpattern comprising peaks, in terms of 2-theta, at 8.6±0.2°, 17.2±0.2°,and 25.9±0.2° and one or more of the following:

-   -   (a) the powder x-ray diffraction pattern further comprising        peaks, in terms of 2-theta, at 23.2±0.2°, and 31.5±0.2°;    -   (b) a melting point of 215±2° C.;    -   (c) a differential scanning calorimetry thermogram comprising a        peak at 215±2° C.;    -   (d) a differential scanning calorimetry thermogram substantially        in accord with FIG. 3B or 3C;    -   (e) a Raman spectra substantially in accord with FIG. 4B, a THz        Raman spectra substantially in accord with FIG. 4E, or both;    -   (f) a chiral purity of greater than about: (i) 90%, (ii)        95%, (iii) 97%, (iv) 99%, (v) 99.5%, (vi) 99.7%, or (vii) 99.9%;    -   (g) a chemical purity of greater than about: (i) 80%, (ii)        90%, (iii) 95%, (iv) 97%, (v) 99%, (vi) 99.5%, (vii) 99.7%,        or (viii) 99.9%; and    -   (h) residual solvents present in an amount less than about: (i)        8000 ppm, (ii) 6000 ppm, (iii) 4000 ppm, (iv) 2000 ppm, (v) 1000        ppm, (vi) 800 ppm, or 500 ppm; and

In some embodiments, provided herein is compound selected from:

-   (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine    besylate,-   (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine    R-mandelate,-   (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine    L-tartrate,-   (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine    D-tartrate,-   (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine    mesylate, and-   (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine    L-malate.

(S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanaminebesylate

Provided herein is(S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanaminebesylate, which is also referred to as (S)-TPMA besylate. In someembodiments, (S)-TPMA besylate is crystalline.

In some embodiments, the crystalline form of (S)-TPMA besylate ischaracterized by a powder x-ray diffraction pattern comprising peaks, interms of 2-theta, at 6.1±0.2°, 12.3±0.2°, and 16.7±0.2°. In someembodiments, the crystalline (S)-TPMA besylate is characterized by apowder x-ray diffraction pattern comprising peaks, in terms of 2-theta,at 6.1±0.2°. In some embodiments, the crystalline (S)-TPMA besylate ischaracterized by a powder x-ray diffraction pattern comprising peaks, interms of 2-theta, at 12.3±0.2°. In some embodiments, the crystalline(S)-TPMA besylate is characterized by a powder x-ray diffraction patterncomprising peaks, in terms of 2-theta, at 16.7±0.2°. In someembodiments, the crystalline (S)-TPMA besylate is further characterizedby the powder x-ray diffraction pattern further comprising a peak, interms of 2-theta, at 19.0±0.2° and 24.7±0.2°. In some embodiments, thecrystalline (S)-TPMA besylate is further characterized by the powderx-ray diffraction pattern further comprising a peak, in terms of2-theta, at two or more of 21.9±0.2°, 22.4±0.2° and 22.8±0.2°.

In some embodiments, the crystalline (S)-TPMA besylate is characterizedby a powder x-ray diffraction pattern substantially in accord with FIG.25.

In some embodiments, the crystalline (S)-TPMA besylate has adifferential scanning calorimetry thermogram comprising a peak at 142±2°C. In some embodiments, the crystalline (S)-TPMA besylate has adifferential scanning calorimetry thermogram substantially in accordwith FIG. 26.

In some embodiments, the crystalline form of (S)-TPMA besylate ischaracterized by a powder x-ray diffraction pattern comprising peaks, interms of 2-theta, at 6.1±0.2°, 12.3±0.2°, and 16.7±0.2°, and a powderx-ray diffraction pattern substantially in accord with FIG. 25. In someembodiments, the crystalline form of (S)-TPMA besylate is characterizedby a powder x-ray diffraction pattern comprising peaks, in terms of2-theta, at 6.1±0.2°, 12.3±0.2°, and 16.7±0.2°, and has a differentialscanning calorimetry thermogram comprising a peak at 142±2° C. In someembodiments, the crystalline form of (S)-TPMA besylate is characterizedby a powder x-ray diffraction pattern comprising peaks, in terms of2-theta, at 6.1±0.2°, 12.3±0.2°, and 16.7±0.2°, and has a differentialscanning calorimetry thermogram substantially in accord with FIG. 26.

In some embodiments, the crystalline (S)-TPMA besylate is characterizedby monoclinic space group P21. In some embodiments, the crystalline(S)-TPMA besylate has unit cell dimensions: a is about 7.7 Å, b is about7.5 Å, c is about 14.8 Å, α is about 90°, β is about 103°, and γ isabout 90°.

In some embodiments, the substance comprising (S)-TPMA besylate wherethe chiral purity of the substance is greater than about 90% (S)-TPMAbesylate. In some embodiments, the substance comprising (S)-TPMAbesylate where the chiral purity of the substance is greater than about95% (S)-TPMA besylate. In some embodiments, the substance comprising(S)-TPMA besylate where the chiral purity of the substance is greaterthan about 97.5% (S)-TPMA besylate. In some embodiments, the substancecomprising (S)-TPMA besylate where the chiral purity of the substance isgreater than about 99% (S)-TPMA besylate.

In some embodiments, the substance comprising (S)-TPMA besylate wherethe chemical purity of the substance is greater than about 90% (S)-TPMAbesylate. In some embodiments, the substance comprising (S)-TPMAbesylate where the chemical purity of the substance is greater thanabout 95% (S)-TPMA besylate. In some embodiments, the substancecomprising (S)-TPMA besylate where the chemical purity of the substanceis greater than about 97.5% (S)-TPMA besylate. In some embodiments, thesubstance comprising (S)-TPMA besylate where the chemical purity of thesubstance is greater than about 99% (S)-TPMA besylate.

(S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamineR-mandelate

Provided herein is(S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamineR-mandelate, which is also referred to as (S)-TPMA R-mandelate. In someembodiments, (S)-TPMA R-mandelate is crystalline.

In some embodiments, the crystalline form of (S)-TPMA R-mandelate ischaracterized by a powder x-ray diffraction pattern comprising peaks, interms of 2-theta, at 9.4±0.2°, 14.3±0.2°, and 16.3±0.2°. In someembodiments, the crystalline (S)-TPMA R-mandelate is characterized by apowder x-ray diffraction pattern comprising peaks, in terms of 2-theta,at 9.4±0.2°. In some embodiments, the crystalline (S)-TPMA R-mandelateis characterized by a powder x-ray diffraction pattern comprising peaks,in terms of 2-theta, at 14.3±0.2°. In some embodiments, the crystalline(S)-TPMA R-mandelate is characterized by a powder x-ray diffractionpattern comprising peaks, in terms of 2-theta, at 16.3±0.2°. In someembodiments, the crystalline (S)-TPMA R-mandelate is furthercharacterized by the powder x-ray diffraction pattern further comprisinga peak, in terms of 2-theta, at 4.7±0.2° and 19.6±0.2°. In someembodiments, the crystalline (S)-TPMA R-mandelate is furthercharacterized by the powder x-ray diffraction pattern further comprisinga peak, in terms of 2-theta, at two or more of 21.8±0.2°, 23.7±0.2° and25.0±0.2°.

In some embodiments, the crystalline (S)-TPMA R-mandelate ischaracterized by a powder x-ray diffraction pattern substantially inaccord with FIG. 11.

In some embodiments, the crystalline (S)-TPMA R-mandelate has adifferential scanning calorimetry thermogram comprising a peak at 129±2°C. In some embodiments, the crystalline (S)-TPMA R-mandelate has adifferential scanning calorimetry thermogram substantially in accordwith FIG. 12.

In some embodiments, the crystalline form of (S)-TPMA R-mandelate ischaracterized by a powder x-ray diffraction pattern comprising peaks, interms of 2-theta, at 9.4±0.2°, 14.3±0.2°, and 16.3±0.2°, and a powderx-ray diffraction pattern substantially in accord with FIG. 11. In someembodiments, the crystalline form of (S)-TPMA R-mandelate ischaracterized by a powder x-ray diffraction pattern comprising peaks, interms of 2-theta, at 9.4±0.2°, 14.3±0.2°, and 16.3±0.2°, and has adifferential scanning calorimetry thermogram comprising a peak at 129±2°C. In some embodiments, the crystalline form of (S)-TPMA R-mandelate ischaracterized by a powder x-ray diffraction pattern comprising peaks, interms of 2-theta, at 9.4±0.2°, 14.3±0.2°, and 16.3±0.2°, and has adifferential scanning calorimetry thermogram substantially in accordwith FIG. 12.

In some embodiments, the substance comprising (S)-TPMA R-mandelate wherethe chiral purity of the substance is greater than about 90% (S)-TPMAR-mandelate. In some embodiments, the substance comprising (S)-TPMAR-mandelate where the chiral purity of the substance is greater thanabout 95% (S)-TPMA R-mandelate. In some embodiments, the substancecomprising (S)-TPMA R-mandelate where the chiral purity of the substanceis greater than about 97.5% (S)-TPMA R-mandelate. In some embodiments,the substance comprising (S)-TPMA R-mandelate where the chiral purity ofthe substance is greater than about 99% (S)-TPMA R-mandelate.

In some embodiments, the substance comprising (S)-TPMA R-mandelate wherethe chemical purity of the substance is greater than about 90% (S)-TPMAR-mandelate. In some embodiments, the substance comprising (S)-TPMAR-mandelate where the chemical purity of the substance is greater thanabout 95% (S)-TPMA R-mandelate. In some embodiments, the substancecomprising (S)-TPMA R-mandelate where the chemical purity of thesubstance is greater than about 97.5% (S)-TPMA R-mandelate. In someembodiments, the substance comprising (S)-TPMA R-mandelate where thechemical purity of the substance is greater than about 99% (S)-TPMAR-mandelate.

(S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamineL-tartrate

Provided herein is(S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamineL-tartrate, which is also referred to as (S)-TPMA L-tartrate. In someembodiments, (S)-TPMA L-tartrate is crystalline.

In some embodiments, the crystalline form of (S)-TPMA L-tartrate ischaracterized by a powder x-ray diffraction pattern comprising peaks, interms of 2-theta, at 6.3±0.2°, 12.7±0.2°, and 19.1±0.2°. In someembodiments, the crystalline (S)-TPMA L-tartrate is characterized by apowder x-ray diffraction pattern comprising peaks, in terms of 2-theta,at 6.3±0.2°. In some embodiments, the crystalline (S)-TPMA L-tartrate ischaracterized by a powder x-ray diffraction pattern comprising peaks, interms of 2-theta, at 12.7±0.2°. In some embodiments, the crystalline(S)-TPMA L-tartrate is characterized by a powder x-ray diffractionpattern comprising peaks, in terms of 2-theta, at 19.1±0.2°. In someembodiments, the crystalline (S)-TPMA L-tartrate is furthercharacterized by the powder x-ray diffraction pattern further comprisinga peak, in terms of 2-theta, at 12.9±0.2°, 16.0±0.2°, 17.1±0.2°, and17.4±0.2°. In some embodiments, the crystalline (S)-TPMA L-tartrate isfurther characterized by the powder x-ray diffraction pattern furthercomprising a peak, in terms of 2-theta, at two or more of 18.1±0.2°,22.9±0.2°, 25.8±0.2°, and 26.3±0.2°.

In some embodiments, the crystalline (S)-TPMA L-tartrate ischaracterized by a powder x-ray diffraction pattern substantially inaccord with FIG. 14. In some embodiments, the crystalline (S)-TPMAL-tartrate has a differential scanning calorimetry thermogram comprisinga peak at 152±2° C.

In some embodiments, the crystalline (S)-TPMA L-tartrate has adifferential scanning calorimetry thermogram substantially in accordwith FIG. 15.

In some embodiments, the crystalline form of (S)-TPMA L-tartrate ischaracterized by a powder x-ray diffraction pattern comprising peaks, interms of 2-theta, at 6.3±0.2°, 12.7±0.2°, and 19.1±0.2°, and a powderx-ray diffraction pattern substantially in accord with FIG. 14. In someembodiments, the crystalline form of (S)-TPMA L-tartrate ischaracterized by a powder x-ray diffraction pattern comprising peaks, interms of 2-theta, at 6.3±0.2°, 12.7±0.2°, and 19.1±0.2°, and has adifferential scanning calorimetry thermogram comprising a peak at 152±2°C. In some embodiments, the crystalline form of (S)-TPMA L-tartrate ischaracterized by a powder x-ray diffraction pattern comprising peaks, interms of 2-theta, at 6.3±0.2°, 12.7±0.2°, and 19.1±0.2°, and has adifferential scanning calorimetry thermogram substantially in accordwith FIG. 15.

In some embodiments, the substance comprising (S)-TPMA L-tartrate wherethe chiral purity of the substance is greater than about 90% (S)-TPMAL-tartrate. In some embodiments, the substance comprising (S)-TPMAL-tartrate where the chiral purity of the substance is greater thanabout 95% (S)-TPMA L-tartrate. In some embodiments, the substancecomprising (S)-TPMA L-tartrate where the chiral purity of the substanceis greater than about 97.5% (S)-TPMA L-tartrate. In some embodiments,the substance comprising (S)-TPMA L-tartrate where the chiral purity ofthe substance is greater than about 99% (S)-TPMA L-tartrate.

In some embodiments, the substance comprising (S)-TPMA L-tartrate wherethe chemical purity of the substance is greater than about 90% (S)-TPMAL-tartrate. In some embodiments, the substance comprising (S)-TPMAL-tartrate where the chemical purity of the substance is greater thanabout 95% (S)-TPMA L-tartrate. In some embodiments, the substancecomprising (S)-TPMA L-tartrate where the chemical purity of thesubstance is greater than about 97.5% (S)-TPMA L-tartrate. In someembodiments, the substance comprising (S)-TPMA L-tartrate where thechemical purity of the substance is greater than about 99% (S)-TPMAL-tartrate.

(S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamineD-tartrate

Provided herein is(S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamineD-tartrate, which is also referred to as (S)-TPMA D-tartrate. In someembodiments, (S)-TPMA D-tartrate is crystalline. In some embodiments,the crystalline form of (S)-TPMA D-tartrate is referred to as Form DA,Form DB, or Form DC.

In some embodiments, the crystalline Form DA of (S)-TPMA D-tartrate ischaracterized by a powder x-ray diffraction pattern comprising peaks, interms of 2-theta, at 7.0±0.2°, 15.0±0.2°, and 17.6±0.2°. In someembodiments, the crystalline Form DA of (S)-TPMA D-tartrate ischaracterized by a powder x-ray diffraction pattern comprising peaks, interms of 2-theta, at 7.0±0.2°. In some embodiments, the crystalline FormDA of (S)-TPMA D-tartrate is characterized by a powder x-ray diffractionpattern comprising peaks, in terms of 2-theta, at 15.0±0.2°. In someembodiments, the crystalline Form DA of (S)-TPMA D-tartrate ischaracterized by a powder x-ray diffraction pattern comprising peaks, interms of 2-theta, at 17.6±0.2°. In some embodiments, the crystallineForm DA of (S)-TPMA D-tartrate is further characterized by the powderx-ray diffraction pattern further comprising a peak, in terms of2-theta, at 12.9±0.2°, 19.5±0.2°, and 20.8±0.2°. In some embodiments,the crystalline Form DA of (S)-TPMA D-tartrate is further characterizedby the powder x-ray diffraction pattern further comprising a peak, interms of 2-theta, at two or more of 21.8±0.2°, 22.0±0.2°, 26.0±0.2°, and27.8±0.2°.

In some embodiments, the crystalline Form DA of (S)-TPMA D-tartrate ischaracterized by a powder x-ray diffraction pattern substantially inaccord with FIG. 17.

In some embodiments, the crystalline Form DA of (S)-TPMA D-tartrate hasa differential scanning calorimetry thermogram comprising a peak at169±2° C. In some embodiments, the crystalline Form DA of (S)-TPMAD-tartrate has a differential scanning calorimetry thermogramsubstantially in accord with FIG. 20.

In some embodiments, the crystalline Form DA of (S)-TPMA D-tartrate ischaracterized by a powder x-ray diffraction pattern comprising peaks, interms of 2-theta, at 7.0±0.2°, 15.0±0.2°, and 17.6±0.2°, and a powderx-ray diffraction pattern substantially in accord with FIG. 17. In someembodiments, the crystalline Form DA of (S)-TPMA D-tartrate ischaracterized by a powder x-ray diffraction pattern comprising peaks, interms of 2-theta, at 7.0±0.2°, 15.0±0.2°, and 17.6±0.2°, and has adifferential scanning calorimetry thermogram comprising a peak at 169±2°C. In some embodiments, the crystalline Form DA of (S)-TPMA D-tartrateis characterized by a powder x-ray diffraction pattern comprising peaks,in terms of 2-theta, at 7.0±0.2°, 15.0±0.2°, and 17.6±0.2°, and has adifferential scanning calorimetry thermogram substantially in accordwith FIG. 20.

In some embodiments, the crystalline Form DB of (S)-TPMA D-tartrate ischaracterized by a powder x-ray diffraction pattern comprising peaks, interms of 2-theta, at 11.6±0.2°, 17.5±0.2°, and 20.7±0.2°. In someembodiments, the crystalline Form DB of (S)-TPMA D-tartrate ischaracterized by a powder x-ray diffraction pattern comprising peaks, interms of 2-theta, at 11.6±0.2°. In some embodiments, the crystallineForm DB of (S)-TPMA D-tartrate is characterized by a powder x-raydiffraction pattern comprising peaks, in terms of 2-theta, at 17.5±0.2°.In some embodiments, the crystalline Form DB of (S)-TPMA D-tartrate ischaracterized by a powder x-ray diffraction pattern comprising peaks, interms of 2-theta, at 20.7±0.2°. In some embodiments, the crystallineForm DB of (S)-TPMA D-tartrate is further characterized by the powderx-ray diffraction pattern further comprising a peak, in terms of2-theta, at 23.4±0.2°, 29.2±0.2°, and 35.8±0.2°. In some embodiments,the crystalline Form DB of (S)-TPMA D-tartrate is further characterizedby the powder x-ray diffraction pattern further comprising a peak, interms of 2-theta, at two or more of 26.9±0.2°, 33.4±0.2°, 35.3±0.2°, and36.7±0.2°.

In some embodiments, the crystalline Form DB of (S)-TPMA D-tartrate ischaracterized by a powder x-ray diffraction pattern substantially inaccord with FIG. 18.

In some embodiments, the crystalline Form DB of (S)-TPMA D-tartrate hasa differential scanning calorimetry thermogram comprising a peak at111±2° C. In some embodiments, the crystalline Form DB of (S)-TPMAD-tartrate has a differential scanning calorimetry thermogramsubstantially in accord with FIG. 21.

In some embodiments, the crystalline Form DB of (S)-TPMA D-tartrate ischaracterized by a powder x-ray diffraction pattern comprising peaks, interms of 2-theta, at 11.6±0.2°, 17.5±0.2°, and 20.7±0.2°, and a powderx-ray diffraction pattern substantially in accord with FIG. 18. In someembodiments, the crystalline Form DB of (S)-TPMA D-tartrate ischaracterized by a powder x-ray diffraction pattern comprising peaks, interms of 2-theta, at 11.6±0.2°, 17.5±0.2°, and 20.7±0.2°, and has adifferential scanning calorimetry thermogram comprising a peak at 111±2°C. In some embodiments, the crystalline Form DB of (S)-TPMA D-tartrateis characterized by a powder x-ray diffraction pattern comprising peaks,in terms of 2-theta, at 11.6±0.2°, 17.5±0.2°, and 20.7±0.2°, and has adifferential scanning calorimetry thermogram substantially in accordwith FIG. 21.

In some embodiments, the crystalline Form DC of (S)-TPMA D-tartrate ischaracterized by a powder x-ray diffraction pattern comprising peaks, interms of 2-theta, at 10.8±0.2°, 15.8±0.2°, and 17.5±0.2°. In someembodiments, the crystalline Form DC of (S)-TPMA D-tartrate ischaracterized by a powder x-ray diffraction pattern comprising peaks, interms of 2-theta, at 10.8±0.2°. In some embodiments, the crystallineForm DC of (S)-TPMA D-tartrate is characterized by a powder x-raydiffraction pattern comprising peaks, in terms of 2-theta, at 15.8±0.2°.In some embodiments, the crystalline Form DC of (S)-TPMA D-tartrate ischaracterized by a powder x-ray diffraction pattern comprising peaks, interms of 2-theta, at 17.5±0.2°. In some embodiments, the crystallineForm DC of (S)-TPMA D-tartrate is further characterized by the powderx-ray diffraction pattern further comprising a peak, in terms of2-theta, at 20.7±0.2° and 23.6±0.2°. In some embodiments, thecrystalline Form DC of (S)-TPMA D-tartrate is further characterized bythe powder x-ray diffraction pattern further comprising a peak, in termsof 2-theta, at two or more of 19.4±0.2°, 21.7±0.2°, and 26.8±0.2°.

In some embodiments, the crystalline Form DC of (S)-TPMA D-tartrate ischaracterized by a powder x-ray diffraction pattern substantially inaccord with FIG. 19.

In some embodiments, the crystalline Form DC of (S)-TPMA D-tartrate hasa differential scanning calorimetry thermogram comprising a peak at185±2° C. In some embodiments, the crystalline Form DC of (S)-TPMAD-tartrate has a differential scanning calorimetry thermogramsubstantially in accord with FIG. 22.

In some embodiments, the crystalline Form DC of (S)-TPMA D-tartrate ischaracterized by a powder x-ray diffraction pattern comprising peaks, interms of 2-theta, at 10.8±0.2°, 15.8±0.2°, and 17.5±0.2°, and a powderx-ray diffraction pattern substantially in accord with FIG. 19. In someembodiments, the crystalline Form DC of (S)-TPMA D-tartrate ischaracterized by a powder x-ray diffraction pattern comprising peaks, interms of 2-theta, at 10.8±0.2°, 15.8±0.2°, and 17.5±0.2°, and has adifferential scanning calorimetry thermogram comprising a peak at 185±2°C. In some embodiments, the crystalline Form DC of (S)-TPMA D-tartrateis characterized by a powder x-ray diffraction pattern comprising peaks,in terms of 2-theta, at 10.8±0.2°, 15.8±0.2°, and 17.5±0.2°, and has adifferential scanning calorimetry thermogram substantially in accordwith FIG. 22.

In some embodiments, the substance comprising (S)-TPMA D-tartrate wherethe chiral purity of the substance is greater than about 90% (S)-TPMAD-tartrate. In some embodiments, the substance comprising (S)-TPMAD-tartrate where the chiral purity of the substance is greater thanabout 95% (S)-TPMA D-tartrate. In some embodiments, the substancecomprising (S)-TPMA D-tartrate where the chiral purity of the substanceis greater than about 97.5% (S)-TPMA D-tartrate. In some embodiments,the substance comprising (S)-TPMA D-tartrate where the chiral purity ofthe substance is greater than about 99% (S)-TPMA D-tartrate.

In some embodiments, the substance comprising (S)-TPMA D-tartrate wherethe chemical purity of the substance is greater than about 90% (S)-TPMAD-tartrate. In some embodiments, the substance comprising (S)-TPMAD-tartrate where the chemical purity of the substance is greater thanabout 95% (S)-TPMA D-tartrate. In some embodiments, the substancecomprising (S)-TPMA D-tartrate where the chemical purity of thesubstance is greater than about 97.5% (S)-TPMA D-tartrate. In someembodiments, the substance comprising (S)-TPMA D-tartrate where thechemical purity of the substance is greater than about 99% (S)-TPMAD-tartrate.

(S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanaminemesylate

Provided herein is(S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanaminemesylate, which is also referred to as (S)-TPMA mesylate. In someembodiments, the crystalline form of (S)-TPMA mesylate is characterizedby DVS of substantially in accord with FIG. 24.

In some embodiments, the substance comprising (S)-TPMA mesylate wherethe chiral purity of the substance is greater than about 90% (S)-TPMAmesylate. In some embodiments, the substance comprising (S)-TPMAmesylate where the chiral purity of the substance is greater than about95% (S)-TPMA mesylate. In some embodiments, the substance comprising(S)-TPMA mesylate where the chiral purity of the substance is greaterthan about 97.5% (S)-TPMA mesylate. In some embodiments, the substancecomprising (S)-TPMA mesylate where the chiral purity of the substance isgreater than about 99% (S)-TPMA mesylate.

In some embodiments, the substance comprising (S)-TPMA mesylate wherethe chemical purity of the substance is greater than about 90% (S)-TPMAmesylate. In some embodiments, the substance comprising (S)-TPMAmesylate where the chemical purity of the substance is greater thanabout 95% (S)-TPMA mesylate. In some embodiments, the substancecomprising (S)-TPMA mesylate where the chemical purity of the substanceis greater than about 97.5% (S)-TPMA mesylate. In some embodiments, thesubstance comprising (S)-TPMA mesylate where the chemical purity of thesubstance is greater than about 99% (S)-TPMA mesylate.

(S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamineL-malate

Provided herein is(S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamineL-malate, which is also referred to as (S)-TPMA L-malate.

In some embodiments, the substance comprising (S)-TPMA L-malate wherethe chiral purity of the substance is greater than about 90% (S)-TPMAL-malate. In some embodiments, the substance comprising (S)-TPMAL-malate where the chiral purity of the substance is greater than about95% (S)-TPMA L-malate. In some embodiments, the substance comprising(S)-TPMA L-malate where the chiral purity of the substance is greaterthan about 97.5% (S)-TPMA L-malate. In some embodiments, the substancecomprising (S)-TPMA L-malate where the chiral purity of the substance isgreater than about 99% (S)-TPMA L-malate.

In some embodiments, the substance comprising (S)-TPMA L-malate wherethe chemical purity of the substance is greater than about 90% (S)-TPMAL-malate. In some embodiments, the substance comprising (S)-TPMAL-malate where the chemical purity of the substance is greater thanabout 95% (S)-TPMA L-malate. In some embodiments, the substancecomprising (S)-TPMA L-malate where the chemical purity of the substanceis greater than about 97.5% (S)-TPMA L-malate. In some embodiments, thesubstance comprising (S)-TPMA L-malate where the chemical purity of thesubstance is greater than about 99% (S)-TPMA L-malate.

(S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine FreeBase

Provided herein is(S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine freebase, which is also referred to as (S)-TPMA, or (S)-TPMA free base. Insome embodiments, (S)-TPMA free base is crystalline.

In some embodiments, the crystalline form of (S)-TPMA free base ischaracterized by a powder x-ray diffraction pattern comprising peaks, interms of 2-theta, at 13.6±0.2°, 16.4±0.2°, 20.0±0.2°, and 20.4±0.2°. Insome embodiments, the crystalline (S)-TPMA free base is characterized bya powder x-ray diffraction pattern comprising peaks, in terms of2-theta, at 13.6±0.2°. In some embodiments, the crystalline (S)-TPMAfree base is characterized by a powder x-ray diffraction patterncomprising peaks, in terms of 2-theta, at 16.4±0.2°. In someembodiments, the crystalline (S)-TPMA free base is characterized by apowder x-ray diffraction pattern comprising peaks, in terms of 2-theta,at 20.0±0.2°. In some embodiments, the crystalline (S)-TPMA free base ischaracterized by a powder x-ray diffraction pattern comprising peaks, interms of 2-theta, at 20.4±0.2°. In some embodiments, the crystalline(S)-TPMA free base is further characterized by the powder x-raydiffraction pattern further comprising a peak, in terms of 2-theta, at22.4±0.2°, 23.2±0.2°, and 27.3±0.2°.

In some embodiments, the crystalline (S)-TPMA free base is characterizedby a powder x-ray diffraction pattern substantially in accord with FIG.32.

In some embodiments, the crystalline (S)-TPMA free base is characterizedby a powder x-ray diffraction pattern comprising peaks, in terms of2-theta, at 13.6±0.2°, 16.4±0.2°, 20.0±0.2°, and 20.4±0.2°, and a powderx-ray diffraction pattern substantially in accord with FIG. 32.

In various aspects, provided are methods for preparing(S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanaminehydrochloride as crystalline Form A. In various embodiments, methods ofmaking (S)-TPMA HCl of Form A begin with(S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine,various other embodiments begin with substantially racemic(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine.

In various aspects, provided are methods for preparing(S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanaminehydrochloride as crystalline Form A with various particle sizedistributions.

Example 1A-1C provides and illustrates various embodiments of methods ofmaking (S)-TPMA HCl of Form A. Example 2 provides and illustratesvarious embodiments of methods of making various particle sizedistributions of (S)-TPMA HCl of Form A.

A synthesis of racemic(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine HCl

is disclosed in U.S. Pat. No. 8,710,245. In the '245 patent, theracemate is resolved into the single (R) and (S) enantiomers:

by column chromatography. The free base of(S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine is ayellow oil that degrades over time when exposed to air.

In various embodiments of the methods of the present inventions, thebalance between polymorphs A and B is driven to substantially purepolymorph Form A by the controlled addition of a solution of betweenabout 5% to about 10% HCl in isopropanol into a solution of (S)-TPMAfree base in isopropanol at a temperature between 20° C. and 60° C.,preferably about 40° C. In various embodiments, the controlled additionis preferably carried out as a logarithmic-like addition where the HClsolution is added slowly at first and the rate is steadily increased.The HCl addition rate, in various embodiments, 10% of the HCl solutionis added over a first time period of between about 10 minutes and about90 minutes, 30% of the HCl solution is added over a second time periodof between about 10 minutes and about 90 minutes, and the remainder ofthe HCl solution is added over a third time period of between about 10minutes and about 90 minutes.

In various embodiments, the slow addition of acid solution (e.g., slowersupersaturation rate) with a logarithmic-like addition profile (examplesinclude, but are not limited to, the Mullin-Nyvlt type addition profile,see, e.g., J. W. Mullin and J. Nývlt, Chem Eng Sci. 1971; 26:3,369-377), higher operation temperature, lower concentration of startingfreebase solution, and higher water content of the crystallizationmixture, favor the generation of large crystals of (S)-TPMA HCl of FormA; whereas lower operation temperature, higher concentration of startingfreebase solution, and lower water content of the crystallizationmixture, favor the generation of smaller crystals of (S)-TPMA HCl ofForm A. It is to be understood, that mean, average and/or medianparticle size is generally not the sole determinant of a desirable PSD,rather, the width of a PSD is often of importance.

The present inventors have also discovered methods of modulating theparticle size distribution of crystalline (S)-TPMA hydrochloride and inparticular of crystalline (S)-TPMA hydrochloride of Form A, into adesired range, for example, a PSD favorable for compressing tabletsand/or providing good solution kinetics. In various embodiments, it hasbeen discovered that the particle size distribution of the (S)-TPMAhydrochloride can be modulated by: (i) the addition rate of HCl duringthe formation of (S)-TPMA HCl (e.g. Step 4b in Scheme 4), (ii). theconcentration of (S)-TPMA freebase in the solution prior to HCl addition(e.g. Compound F concentration in Scheme 4 between Steps 4a and 4b);(ii) the temperature of the solution during HCl addition; (iv) the watercontent of the crystallization mixture; and (v) the reaction process.

Referring to FIGS. 7A, 7B, 8A, 8B, 8C, and 9A, presented are various PSDdata for (S)-TPMA HCl of Form A, obtained under various conditions asfurther discussed in Example 2. The PSD data of FIGS. 7A, 7B, 8A, 8B and8C was obtained by a laser diffraction particle sizing technique using aMalvern Mastersizer 2000 analyzer instrument and the PSD data of FIG. 9Aby a laser diffraction particle sizing technique using a Horiba LA-920instrument, and all data is presented as volume % as a function ofparticle size.

It has been discovered that, the PSD of crystals of (S)-TPMA HCl of FormA can in various embodiments be affected by the supersaturationgeneration rate (e.g. controlled by the dosing profile of the HClsolution Step 4b of Scheme 4), operation temperature, water content, andreaction process (e.g. mixing, sonication, etc.). For example, invarious embodiments, it has been discovered that sonication duringaddition of HCl to form (S)-TPMA HCl (e.g. Step 4b in Scheme 4) candramatically decrease the final (S)-TPMA HCl crystal size (e.g. D50=20to 30 μm) of Form A by promoting the nucleation over the course ofaddition of HCl.

In various embodiments, of the reactive-crystallization of (S)-TPMA HCl,the supersaturation generation rate can be directly controlled by theHCl solution addition rate; faster dosing (HCl addition) favoring theformation of smaller crystals and slower dosing favoring the formationof larger crystals. However, faster addition results in wider PSDdistributions.

In various embodiments, operational temperature can be used to affectthe kinetic behavior for nucleation and crystal growth, as well assolubility. It has been discovered that higher temperature increasesmean crystal size and width of the PSD.

In various embodiments, starting (S)-(−)-TPMA freebase concentrationprior to reactive recrystallization can be used to affect the kineticbehavior for nucleation and crystal growth. It has been discovered thathigher starting (S)-(−)-TPMA freebase concentration decreased both themedian particle size and the width of the PSD.

While the solvent in the experiments described in Example 1A, and above,was isopropanol, the temperature/solubility, in various embodiments,alkyl alcohols of 4 carbons or less, including but not limited to,n-propanol, isopropanol, and n-butanol can be used.

In various embodiments, the (S)-TPMA free base is dissolved in a solventsystem comprising from 90% to 100% isopropanol.

In various embodiments, the solvent system is 90% to 99% isopropanol andthe remainder is water. In various embodiments the solvent system is 93%to 97% isopropanol and the remainder is water.

In various embodiments, the solvent system is >99% isopropanol. Thepresence of water, in various embodiments, of up to about 5% leads tocrystals of (S)-TPMA HCl polymorph Form A that are more cubic thanhexagonal in morphology. In various embodiments, the methods of thepresent inventions provide for (S)-TPMA HCl crystals of Form A withincreased cubic morphology. In various embodiments of the composition,medicaments and formulations of the present inventions, (S)-TPMA HClcrystals of Form A with increased cubic morphology are preferred asbeing more flowable than the hexagonal morphology, and as possessingadvantages in formation of certain solid oral dosage forms, e.g., incertain tableting operations.

In Example 1A, the hydrogen chloride in isopropanol was prepared at 6%by weight, but could be employed in other concentrations; for example,in various embodiments from about 4% to about 10%. In variousembodiments, the HCl in an alkyl alcohol of 4 carbons or less, e.g.isopropanol, can be added in ratios from 1.0 to 1 up to 1.2 to 1stoichiometry based on the amine in (S)-TPMA.

The concentration of (S)-TPMA free base in the alkyl alcohol of 4carbons or less, e.g. isopropanol, was observed to be operable over awide range. In various embodiments, the concentration of (S)-TPMA freebase solution is between about 5.0% to 25.0% by weight %, and preferablybetween about 10% and about 15%. In various embodiments, theconcentration of (S)-TPMA free base solution is about 10.0%, about11.0%, about 13.0%, or in some, about 15.0% by weight %.

With references to the teachings herein the skilled artisan wouldunderstand that very dilute solutions of (S)-TPMA free base are likelyto produce lower yields because of the finite solubility of (S)-TPMAhydrochloride in alkyl alcohols of 4 carbons or less, e.g. isopropanol.

In some embodiments, the particle size distribution of crystals of(S)-TPMA HCl of Form A can be controlled by the balance among thereactant addition rate, local and global supersaturation, mass transferand crystal surface area. It was discovered that the slow addition ofacid solution, for example, with a Mullin-Nyvlt-like addition profile,higher operation temperature, lower concentration of starting freebasesolution, presence of water in the solvent system, seeding favors theformation of the larger polymorph Form A (S)-TPMA HCl crystals, andsonication during supersaturation favors the formation of the smallerpolymorph Form A (S)-TPMA HCl crystals.

In various embodiments, provided are compounds comprising Form Acrystals of (S)-TPMA HCl having a particle size distribution (whenmeasured by laser diffraction, for example, as set forth in Example 2)with a median (D50) between about 15 μm to about 30 μm, a D10 greaterthan about 10 μm and a D90 less than about 40 μm; and preferably with aD50 between about 20 μm to about 30 μm.

In various embodiments, provided are compounds comprising Form Acrystals of (S)-TPMA HCl having a particle size distribution (whenmeasured by laser diffraction, for example, as set forth in Example 2)with a median (D50) between about 15 μm to about 30 μm, (and preferablybetween about 20 μm to about 30 μm), and a span less than about 1.75,less than about 1.5, less than about 1, or less than about 0.8.

In various embodiments, provided are compounds comprising Form Acrystals of (S)-TPMA HCl having a particle size distribution (whenmeasured by laser diffraction, for example, as set forth in Example 2)with a median (D50) between about 100 μm to about 135 μm (and preferablya D50 between about 100 μm to about 110 μm), a D10 greater than about 60μm and a D90 less than about 165 μm; and preferably with a D10 greaterthan about 70 μm and a D90 less than about 150 μm.

In various embodiments, provided are compounds comprising Form Acrystals of (S)-TPMA HCl having a particle size distribution (whenmeasured by laser diffraction, for example, as set forth in Example 2)with a median (D50) between about 100 μm to about 135 μm (and preferablya D50 between about 100 μm to about 110 μm), and a span less than about1.75, less than about 1.5, less than about 1, or less than about 0.8.

In various embodiments, provided are compounds comprising Form Acrystals of (S)-TPMA HCl having a particle size distribution (whenmeasured by laser diffraction, for example, as set forth in Example 2)with a median (D50) between about 135 μm to about 180 μm (and preferablya D50 between about 160 μm to about 170 μm), a D10 greater than about100 μm and a D90 less than about 250 μm; and preferably with a D10greater than about 110 μm and a D90 less than about 230 μm.

In various embodiments, provided are compounds comprising Form Acrystals of (S)-TPMA HCl having a particle size distribution (whenmeasured by laser diffraction, for example, as set forth in Example 2)with a median (D50) between about 135 μm to about 180 μm (and preferablya D50 between about 160 μm to about 170 μm), and a span less than about1.75, less than about 1.5, less than about 1, or less than about 0.8.

In various embodiments, provided are compounds comprising Form Acrystals of (S)-TPMA HCl having a particle size distribution (whenmeasured by laser diffraction, for example, as set forth in Example 2)with a median (D50) between about 180 μm to about 230 μm (and preferablya D50 between about 190 μm to about 220 μm), a D10 greater than about110 μm and a D90 less than about 350 μm; and preferably with a D10greater than about 120 μm and a D90 less than about 340 μm.

In some embodiments, D10 is greater than about 50 μm. In someembodiments, D10 is greater than about 75 μm. In some embodiments, D10is greater than about 80 μm. In some embodiments, D10 is greater thanabout 90 μm. In some embodiments, D10 is greater than about 100 μm. Insome embodiments, D10 is greater than about 110 μm. In some embodiments,D10 is greater than about 120 μm. In some embodiments, D10 is greaterthan about 130 μm. In some embodiments, D10 is greater than about 150μm. In some embodiments, D90 is greater than about 200 μm. In someembodiments, D90 is greater than about 250 μm. In some embodiments, D90is greater than about 300 μm. In some embodiments, D90 is greater thanabout 350 μm. In some embodiments, D90 is greater than about 400 μm. Insome embodiments, the median (D50) is in the range in any of theembodiments provided herein, e.g., between about 50 μm to about 400 μm,between about 100 μm to about 300 μm, between about 120 μm to about 300μm, etc.

In various embodiments, provided are compounds comprising Form Acrystals of (S)-TPMA HCl having a particle size distribution (whenmeasured by laser diffraction, for example, as set forth in Example 2)with a median (D50) between about 180 μm to about 230 μm (and preferablya D50 between about 190 μm to about 220 μm), and a span less than about1.75, less than about 1.5, less than about 1, or less than about 0.8.

In various embodiments, the methods of the present inventions providefor Form A crystals of (S)-TPMA HCl having a PSD (when measured by laserdiffraction, for example, as set forth in Example 2) with a median (D50)between about 15 μm to about 30 μm, a D10 greater than about 10 μm and aD90 less than about 40 μm; and preferably with a D50 between about 20 μmto about 30 μm, a D10 greater than about 10 μm and a D90 less than about40 μm; where the methods comprise sonication during a step ofsupersaturation of a freebase solution of (S)-TPMA to form (S)-TPMA HCl.

In various embodiments, the methods of the present inventions providefor Form A crystals of (S)-TPMA HCl having a PSD (when measured by laserdiffraction, for example, as set forth in Example 2) with a median(D50), in various embodiments, between about 100 μm to about 230 μm,between about 100 μm to about 135 μm, between about 135 μm to about 180μm, or between about 180 μm to about 230 μm; and having a span less thanabout 1.75, less than about 1.5, less than about 1, or less than about0.8; where the methods comprise using a logarithmic-like addition of HClduring the reactive-recrystallization of (S)-TPMA to form (S)-TPMA HCl.In various embodiments, the logarithmic-like addition comprises additionof between about 10% to about 15% of an HCl solution over a first timeperiod, addition of about 30% to about 40% of the HCl solution over asecond time period after the first time period, and addition of theremainder (between about 45% to about 60%) of the HCl solution over athird time period after the second time period. In various embodiments,the first, second and third time periods are independently in the rangebetween about 10 minutes to about 90 minutes. In various embodiments,the first, second and third time periods are substantially equal within±10% of each other.

In various aspects, provided are methods for preparing(S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanaminehydrochloride as crystalline Form A. In various embodiments, the methodcomprises:

-   -   (a) dissolving        (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine        free base in a solvent system comprising an alkyl alcohol of 4        carbons or less;    -   (b) adding excess HCl in an alkyl alcohol of 4 carbons or less;        and    -   (c) isolating crystalline        (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine        hydrochloride. In various embodiments, the alkyl alcohol is one        or more of n-propanol, isopropanol, and n-butanol, and in        various embodiments, the alkyl alcohol is preferably        isopropanol.

In various embodiments of methods for preparing(S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanaminehydrochloride as Form A, the method comprises:

-   -   (a) combining        racemic-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine        with a stoichiometric excess of (R)-mandelic acid in a solvent;    -   (b) isolating        (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine        R-mandelate salt;    -   (c) freeing        (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine        from the (R)-mandelate salt;    -   (d) dissolving the        (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine        in a solvent system comprising an alkyl alcohol of 4 carbons or        less;    -   (e) adding HCl in an alkyl alcohol of 4 carbons or less; and    -   (f) isolating crystalline        (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine        hydrochloride. In various embodiments, the alkyl alcohol is one        or more of n-propanol, isopropanol, and n-butanol, and in        various embodiments, the alkyl alcohol is preferably        isopropanol.

A synthesis of (S)-TPMA hydrochloride is disclosed in U.S. Pat. No.8,710,245. The synthesis procedure reported in the '245 patent is usedto produce small quantities of the compound. This procedure requireschromatographic separations, which is typically not suitable for largescale manufacture. For instance, normal phase or chiral phasechromatographic separations are not practical for the large scalemanufacture. Resolution procedures are developed to replace chiralchromatographic separations. Resolution procedures are robust,practical, easy to scale up and are routinely used in production ofchiral of compounds at various scales. In the large scale preparation of(S)-TPMA hydrochloride, a R-mandelic acid mediated resolution of(S)-TPMA free base to replace chiral chromatographic separation ofN-Boc-TPMA was developed.

The procedure in the '245 patent is performed on 1 g scale. The work upof reaction involved neutralization of the product (S)-TPMA triflatesalt with potassium carbonate and the resulting free base was treatedwith methanolic HCl to produce (S)-TPMA HCl salt that was isolated afteraddition of anti-solvent MTBE. The process described herein provided(S)-TPMA triflate with high purity. Typically, (S)-TPMA triflate isobtained with 76-80% yield with >99.2% purity. The process describedherein is shorter as there is no need to make free base and furtherconvert it to (S)-TPMA HCl salt. 2-methyl THF is suitable solvent forthis step. MTBE is used as an anti-solvent for the crystallization step.2-methyl THF is a green solvent that is highly desirable than the ClassII solvent 1,4-dioxane used in the process in the '245 patent.

In some embodiments, provided herein is a method of preparing(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine, whereinthe method comprises

-   -   (a) reacting 2-(thiophen-3-yl)ethan-1-ol with        N-methylaminoacetaldehyde dimethylacetal and triflic acid to        provide        (4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine        triflate; and    -   (b) reacting        (4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine        triflate with a base to provide        (4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine.

In some embodiments, provide herein is a method of preparing(S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine,wherein the method comprises:

(a) reacting 2-(thiophen-3-yl)ethan-1-ol with N-methylaminoacetaldehydedimethylacetal and triflic acid to provide(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine triflate;

(b) reacting(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine triflatewith a base to provide(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine;

(c) reacting(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine with(R)-mandelic acid to provide(S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine(R)-mandelate; and

(d) reacting(S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine(R)-mandelate with a base to provide(S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine.

In some embodiments, provided herein is a method of preparing salts of(S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine,wherein the method comprises reacting(S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine with anacid. For example, reacting(S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine withHCl would generate the corresponding HCl salt.

In some embodiments, provided herein is a method of preparing(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine triflate.In some embodiments, the method comprises reacting2-(thiophen-3-yl)ethan-1-ol with N-methylaminoacetaldehydedimethylacetal and triflic acid to provide(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine triflate.In some embodiments, the reacting can be carried out in the presence ofa solvent. The solvent can be an ether such as 2-methyl tetrahydrofuran.In some embodiments, the reacting of 2-(thiophen-3-yl)ethan-1-ol withN-methylaminoacetaldehyde dimethylacetal and triflic acid is carried outat temperature of about 50° C. to 100° C. In some embodiments, thetemperature is about 75° C. to 85° C., e.g., 80° C. In some embodiments,the method comprises reacting 2-(thiophen-3-yl)ethan-1-ol with sulfuricacid, N-methylaminoacetaldehyde dimethylacetal and triflic acid.

In some embodiments, provided herein is a method of preparing(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine. In someembodiments, the method comprises reacting(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine triflatewith a base to provide(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine. In someembodiments, the base is an alkali metal base such as KOH. In someembodiments, the reacting is carried out in the presence of a solvent.The solvent can be an ether such as methyl t-butyl ether.

In some embodiments, provided herein is a method of preparing(S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine(R)-mandelate. In some embodiments, the method comprises reacting(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine with(R)-mandelic acid to provide(S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine(R)-mandelate. In some embodiments, the reacting is carried out in polaraprotic solvent such as acetonitrile and acetone, or a mixture thereof.

In some embodiments, provided herein is a method of preparing(S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine. Insome embodiments, the method comprises reacting(S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine(R)-mandelate with a base to provide(S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine. Insome embodiments, the base is an alkali metal base such as KOH. In someembodiments, the reacting is carried out in a solvent. The solvent canbe an ether or water, or a mixture thereof. In some embodiments, theether is methyl t-butyl ether.

Example 1A: Preparation of(S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine HCl ofCrystalline Form A

77 g of 3-thiopheneethanol (Compound A) was added to a solution of 69 gof N-methylaminoacetadehyde dimethyl acetal in 595 ml (508 g) of2-methyl tetrahydrofuran (2Me THF). After stirring for 5 minutes 99 g(58.2 ml) trifluoromethanesulfonic acid was added. It is important tonote that trifluoromethanesulfonic acid is a very hazardous substance.The reaction was heated to reflux for 1 hour (80±2° C.). The reactionwas then distilled at atmospheric pressure to remove the byproductmethanol and to reduce the reaction volume to a targeted volume of 460ml over 4-8 hours. The reaction was judged complete when 1.0% or less(HPLC Peak Area % of peaks of interest, Compounds A, B and C) ofcompound 1B remained by a sample HPLC analysis.

If the amount of Compound B was greater than or equal to 1%, anappropriate amount of 2-methyl THF was added and distillation continuedto the target volume. If the target volume was reached before thecompletion of reaction (about 4 hours), 300 ml 2-methyl THF was added tothe reaction for continuation of the distillation. After reactioncompletion, the reaction was cooled to about 40-50° C. and concentratedto a target volume of 325 ml under vacuum distillation. 218 g (325 ml)of Toluene was then added over about 15 minutes and the reaction slurryformed was then stirred for 1 hour at 50±2° C., and then cooled to 20±2°C. linearly over 1 hour 45 minutes while being stirred. The slurry wasfiltered and the product cake was washed with a 2-methyl THF and toluenemixture (1:1 volume/volume). The wet-cake was dried under vacuum at40±5° C. to constant weight to yield racemic TPMA triflate (Compound C)as an off-white solid and a yield of about 79% was obtained.

In various embodiments, di-p-toluoyl-D-tartaric acid (D-DTTA) was usedas the resolving agent to produce a (S)-TPMA-D-DTTA salt and the presentinventors discovered that use of D-DTTA provided for a kinetic basedresolution. However, Scheme 2 of the present example provides for use of(R)-mandelic acid and the present inventors discovered thatdiasteromeric crystallization with (R)-mandelic acid is a thermodynamicbased separation.

To a suspension of 555.3 g of TPMA triflate (Compound 1C) in 1668 mlmethyl tert-butyl ether (MTBE) was added 1076 g of 1.77 N aqueous KOH.After stirring for 10 minutes the pH was checked and if less than 13,small portions of 1.77 N KOH were added until the pH was 13 or greater.The aqueous and organic layers were allowed to settle and separate andseparately collected. The MTBE (upper) organic phase layer was held forfurther processing. The aqueous (bottom) phase layer was extracted twicewith MTBE (first with 835 ml and second with 150 ml), the organic (MBTE)layer being collected each time. The MTBE layers (organic layers) werecombined, and washed with 20% aqueous NaCl solution (492.9 g) stirredand the phases allowed to settle for 10 minutes. The aqueous layer wasremoved and the remaining MTBE organic layer was distilled atatmospheric pressure to reduce the reaction volume to a targeted levelof 1.9 L. After completion, the process stream was cooled to about 45°C. and concentrated to a target volume of 890 ml under vacuumdistillation while maintaining the temperature at 35-45° C. The watercontent after vacuum distillation was found to be about 0.37% by weight.A filtration was then performed to remove insoluble materials using awash of 204 ml MTBE, and the process stream (filtrate) was transferredto a clean reactor. 2512 mL of acetonitrile was added and a solventswitch was performed via vacuum distillation at 35-45° C. to thetargeted volume of 800 ml, and the reactor washed with 150 ml ofacetonitrile and added to the process stream. Acetonitrile was thenadded, if needed, to the acetonitrile solution of TPMA free base(Compound D) to achieve about a 33 weight % of Compound D.

A solution of 250.3 g of (R)-mandelic acid in 1828 ml of acetone waswarmed to 48±2° C. The acetone solvent can be replaced withacetonitrile. The TPMA free base solution in acetonitrile (917.7 gsolution of 302.1 g of Compound D in acetonitrile) was then added at arate maintaining the reaction temperature below 51° C. After stirring at48±2° C. for about 10 minutes the process stream was cooled to 45±2° C.and charged with 1.5 g of (S)-TPMA (R)-mandelate seed crystals. Theprocess stream was stirred at 45±2° C. for about 30 minutes and cooledlinearly to 21±2° C. over 90 minutes. After holding at 45±2° C. forabout 30 minutes the process stream was cooled linearly to 10±2° C. over45 minutes. The reaction slurry was then stirred for 60 minutes at 10±2°C., filtered and the product cake was washed with acetone/CH₃CN mixture(2.3:1 weight/weight). The wet-cake was dried under vacuum at 40±2° C.to a constant weight to yield crude (S)-TPMA (R)-mandelate (Compound E)as a white crystalline solid, and a yield of about 41% was obtained.

Scheme 3 presents a process for the recrystallization of(S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine (R)mandelate, ((S)-TPMA (R)-mandelate). It is to be understood that variousother recrystallization solvents can be used. Scheme 3 of the presentexample provides for use of acetone and the present inventors havediscovered that acetone can provide a combination of sufficiently highyield and effective rejection of key impurities. In various embodiments,the amount of acetone was selected based on solubility of (S)-TPMA(R)-mandelate in acetone at reflux temperature, preferably the minimumamount of acetone required for dissolution of crude (S)-TPMA(R)-mandelate at reflux was used. In various embodiments, the solvent isacetonitrile instead of acetone, where (S)-TPMA (R)-mandelate isdissolved at about 52±2° C. In various embodiments, Scheme 3 is aseed-induced crystallization and is conducted with linear cooling from47±2° C. to 21±2° C. over 90 minutes followed by a hold for 30 minutesat 21±2° C., followed by linear cooling to 10±2° C. over 45 minutes anda hold at 10±2° C. preferably for a minimum of 1 hour.

A slurry of crude (S)-TPMA (R)-mandelate (Compound E) from Scheme 2(200.1 g) in 4205 ml of acetone was warmed to about 56° C. (boilingpoint of acetone) and stirred until a clear solution was obtained. Aftercooling the solution to 47±2° C. over approximately 20 minutes (S)-TPMA(R)-mandelate seed crystals were added. The process stream was stirredat 47±2° C. for about 30 minutes and cooled linearly to 21±2° C. over 90minutes. After holding at 21±2° C. for about 30 minutes the slurry wascooled linearly to 10±2° C. over 45 minutes and then stirred for 1 hourat 10±2° C., filtered, and the product cake was washed with acetone(twice with 401 ml each time). The wet-cake was dried under vacuum atabout 40±2° C. to a constant weight to yield (S)-TPMA (R)-mandelate(purified Compound E) as a white crystalline solid, and a yield of about77% was obtained.

Scheme 4 of the present example provides a reactive crystallization of(S)-(−)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamineHCl, ((S)-TPMA HCl), as crystalline Form A. The present inventors havediscovered that as (S)-TPMA HCl crystallizes it displays two distinctmorphologies (polymorphs), the first a block like crystal (Form A) andthe second a needle like crystal (Form B). Based on single crystal x-raydiffraction studies, described herein, Form A has a monoclinic crystalsystem while Form B has an orthorhombic crystal system. The presentinventors have discovered that Form A is the stable form under thereaction conditions of the present example and have discovered how toavoid formation of Form B. In various embodiments, (S)-TPMA(R)-mandelate is first converted to the free base and HCl added to forma slurry.

To a suspension of(S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine(R)-mandelate salt (Compound E) from Scheme 3 (100 g) in 305 ml of MTBE,172.5 ml of a 10% KOH aqueous solution was added. After stirring for 10minutes at 20±2° C. the aqueous and organic layers were separated. Theorganic MTBE (upper) layer was saved for further processing. If the pHof the aqueous layer was less than 13, small portions of the 10% KOHsolution were added to raise the pH to 13. The aqueous (bottom) layerwas back extracted twice with MTBE (first with 208 ml MTBE, second with155 ml MTBE), the organic layer being saved for further processing eachtime. The saved organic layers were combined, and the combined organiclayer was subjected to azeotropic distillation to remove water anddistilled at atmospheric pressure to a target volume of 140 ml. Theprocess stream was then filtered, to remove insoluble material (e.g.salt precipitated due to removal of water), and the filtrate transferredto a clean reactor. 775 ml of Isopropanol was added (resulting in atotal process stream volume of about 1030 ml) and a solvent switch wasperformed via vacuum distillation at less than 45° C. to provide a16-19% solution of(S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine inisopropanol.

In various embodiments, the amount of isopropanol added was selected soto adjust the freebase (Compound F) weight % concentration to 16-19%.The reaction mixture was cooled to 20±2° C., polish filtered, the filterwashed with 78 ml isopropanol, and the filtrate transferred to a cleanreactor. 201.6 g of a 6% HCl (w/w) solution in isopropanol was thenadded into the reactor over 45 minutes at about 20±2° C. It is to beunderstood that in various embodiments, the target amount of HCl isabout 10% excess relative to the freebase (Compound F) molarequivalence. The HCl was added as follows, the first 10% was added over15 mins., the next 30% was added over 15 mins, and the remainder wasthen added over 15 mins. A retreat curve impeller at 160 rpm to 270 rpmin a 5 L scale reactor was used, with a process stream volume of about740 ml, and produced reasonable-sized particles and particledistributions with no obvious agglomeration observed. The slurry formedwas warmed up to 40±2° C. linearly over 20 minutes and held at 40±2° C.for about 30 minutes. It was then cooled linearly to 20±2° C. over 20minutes. After stirring at 20±2° C. for about 30 minutes the slurry wasfiltered and the product cake was washed with isopropanol (first with 86ml, second with 92 ml). The cake was dried under vacuum at 40±2° C. to aconstant weight to yield (S)-(−)-TPMA hydrochloride (Compound G) as awhite crystalline solid, and a yield of about 84% was obtained.

In Step 4b of Scheme 4, slow addition, that results in lowsupersaturation generation rate, favors the formation of desired block(S)-(−)-TPMA HCl crystals (Form A) while decreasing the generation theundesired needles (Form B). Higher temperature also favored theformation of the block like Form A crystals over Form B.

An ¹H NMR spectrum of the(S)-(−)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanaminehydrochloride (Compound G) obtained in Example 1A is illustrated in FIG.10, having the following characteristics: ¹H NMR (300 MHz, DMSO-d₆); δ(ppm): 2.53 (s, 3H, —CH₃); 2.5-2.8 (m, H, —CH₂—); 3.15-3.37 (2dd, 2H,CH₂—NH); 3.77 and 4.13 (2ddd, 2H, CH₂—O); 5.19 (dd, 1H, O—CH—C═); 6.95(d, J=5 Hz, 1H, HC═); 7.49 (dd, J=5 Hz, 1H, HC═); 9.12 (br, 2H, NH₂ ⁺).

Example 1B: Alternative Preparation of(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine triflate

2-(Thiophene-3-yl)ethanol (40 g, 0.31 mole) was placed in a 1 L reactorequipped with a mechanical stirrer, N₂ inlet and thermocouple.N-methylaminoacetaldehyde dimethylacetal (38.8 g, 0.28 mole) and 600 mLof 2-methyltetrahydrofuran were added. The resulting solution was cooledto about 5° C. Sulfuric acid (111.3 g, 1.13 mole) was added slowly whilemaintaining the reaction temperature below 20° C. The reaction waswarmed to 35° C. and stirred for 4 hours. The HPLC examination of thereaction indicated about 31% formation of the product(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine (TPMA). Thereaction was cooled to room temperature and solvent was removed undervacuum. The resulting residue diluted with 300 mL of methyltertbutylether (MTBE). The mixture was cooled to about 10° C. and 500 mL25 wt % aq. NaOH was added while maintaining the reaction temperaturebelow 30° C. The mixture was stirred for 20 minutes the layers wereseparated. The aqueous layer was extracted with twice (150 mL and 100mL) with MTBE. The combined organic layer was then concentrated viaremoval of solvent by distillation. The concentrated organic layer wasthen cooled to 0° C. and 20 g (0.13 mol) of triflic acid was then addedslowly while maintaining the reaction temperature below 10° C. Theresulting slurry was stirred at 0° C. for 30 minutes. The slurry wasfiltered, and wet cake was washed with MTBE (2×20 mL), dried in vacuo togive TPMA-triflate salt as white solid (13.0 g, 13.75% yield with 97%purity).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.62 (s, 3H) 2.64-2.76 (m, 2H) 3.22 (dd,J=12.91, 9.78 Hz, 1H) 3.40 (dd, J=12.91, 2.74 Hz, 1H) 3.79 (ddd,J=11.54, 8.80, 4.30 Hz, 1H) 4.00-4.20 (m, 1H) 5.09 (dd, J=9.59, 1.76 Hz,1H) 6.95 (d, J=5.09 Hz, 1H) 7.50 (d, J=5.02 Hz, 1H) 8.59 (br s, 2H)

¹³C NMR (101 MHz, DMSO-d₆) δ ppm 25.53, 33.02, 52.19, 62.73, 70.23,124.62, 127.54, 131.01, 134.87.

Example 1C. Alternative Preparation of(S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine (R)Mandelate Salt

To a slurry of 1.0 g (3.0 mmole) of TPMA-triflate in 3 mL MTBE 10% KOH(0.217 g in 2 mL water, 3.8 mmole) was added and stirred for 15 min.Organic layer was separated and aq. layer was extracted with MTBE (2×3mL). Combined organic layer was washed with 1×2 mL of 20 wt % aqueousNaCl. Organic layer was dried over sodium sulfate, filtered andevaporated to dryness to give(S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine freebase as colorless oil (0.473 g, 86.2%). This was dissolved into 2.4 mLacetonitrile and added to a solution of 0.392 g (2.5 mmole) ofR-mandelic acid in 2.4 mL of acetonitrile. The resulting solution washeated to 38° C. and seeded with 15 mg of(S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine (R)mandelate salt crystals, stirred for 30 min at 38° C. and cooled to RTand then to 10° C. The slurry was stirred at 10° C. for 30 minutes andfiltered. Wet cake was washed with cold (10° C.) acetonitrile, 2×1 mL,dried to afford crude (S)-TPMA (R)-mandelate salt as white solid (0.292g, 33.75% yield, 96% purity, 9.3:91.7 ratio of R:S isomers)

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.49 (s, 3H), 2.57-2.79 (m, 2H)3.00-3.17 (m, 2H) 3.69 (ddd, J=11.64, 8.90, 4.50 Hz, 1H) 4.08 (ddd,J=11.35, 5.48, 3.52 Hz, 1H) 4.66 (s, 1H) 4.89-5.07 (m, 1H) 6.91 (d,J=4.70 Hz, 1H) 7.13-7.32 (m, 3H) 7.36-7.44 (m, 3H)

¹³C NMR (101 MHz, DMSO-d₆) δ ppm 25.63, 33.72, 53.42, 62.70, 71.26,73.20, 124.23, 126.36, 126.42, 127.29, 127.52, 132.48, 134.24, 142.85,174.78.

Example 2: Particle Size Distribution Control of(S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine HClForm A Crystals

A series of experiments was conducted on various aspects of thereactive-recrystallization (e.g. Scheme 4 in Example 1A) to developmethods and provide various particle size distribution of (S)-(−)-TPMAHCl Form A crystals. Reaction conditions were substantially similar tothose set for in Example 1A with respect to Scheme 4 except as modifiedas described in this Example 2.

The PSD data of this Example 2 was obtained using laser diffractionparticle sizing of the sample dispersed in a solvent. The data of FIGS.7A, 7B, 8A, 8B and 8C was obtained using a Malvern Mastersizer 2000analyzer, and the data of FIG. 9A was obtained using a Horiba LA-920laser diffraction particle size analyzer. All particle sizes and D(4,3),D10, D50, D90, etc. values are in micrometers (μm), and alldistributions are for volume % as a function of particle size.

The (S)-TPMA HCl sample was dispersed in a solution of Span®-85(sorbitan trioleate) and hexanes. In this Example, the dispersantsolution was 2 g of Span®-85 in 1 liter of hexanes, to make a 0.2% (w/v)Span®-85 in hexanes solution. All samples were gently sieved through a#30 mesh screen prior to addition to the dispersant solution.

The suspension solution for analysis was prepared by addition ofapproximately 5 mL of the 0.2% Span®-85 in hexanes dispersant solutionto 1.5 to 3 grams of the sieved (S)-TPMA HCl sample, and the solutiongently swirled until all of the solids were wetted. Then 35 mL of the0.2% Span®-85 in hexanes dispersant solution was added and the solutionmixed for at least 1 minute prior to measurement with an impeller set to500 rpm to make the suspension solution. The actual amount of (S)-TPMAHCl sample, to which the dispersant solution is added, was determinedexperimentally and adjusted such that 2 to 3 mL of the resultantsuspension solution will result in a laser obscuration between 10% and20% as measured by the instrument used.

Prior to measurement, the instrument was aligned and backgroundmeasured, and 2-3 mL of the suspension solution transferred to thesample cell of the instrument for measurement.

The data of FIGS. 7A, 7B, 8A, 8B and 8C was obtained using a MalvernMastersizer 2000 analyzer, and Table 6 provides further details on theinstrument settings of the Malvern Mastersizer 2000 analyzer used inthis Example. Corresponding and similar setting were used on the HoribaLA-920 laser diffraction particle size analyzer used to acquire the dataof FIG. 9A, specifically, PSD data generated on the Horiba LA-920 used3% lecithin in Isopar G.

TABLE 6 Malvern Mastersizer 2000 Analyzer Instrument Settings ParameterSetting Stirrer/Pump Speed 1750 rpm Ultrasound 0 Sample Refractive Index1.5 (red and blue light) Sample Absorption 0 (red and blue light)Dispersant name 0.2% Span 85 in hexanes Dispersant Refractive Index 1.38Model General Purpose-normal sensitivity Sample measurement time 30seconds Sample measurement snaps 30000 Background measurement time 30seconds Background measurement snaps 30000 Number of measurement cycles1

Modulation by Supersaturation Generation Rate

The (S)-(−)-TPMA freebase containing solution (e.g. solution of CompoundF in Scheme 4) was reactively-recrystallized as a crystalline form ofthe (S)-(−)-TPMA HCl salt by addition of an HCl in isopropanol (IPA) toform a super saturated (S)-(−)-TPMA HCl from which crystallizationoccurred. FIGS. 6A and 6B present various 6% HCl in IPA additionprofiles, which are also summarized in Table 7. Measured resultant PSDfor the addition profiles of FIGS. 6A and 6B are presented respectivelyin FIGS. 7A and 7B. Table 8 provides various PSD parameters of the PSDdata presented in FIGS. 7A and 7B.

It was discovered that a logarithmic-like addition of the reagent (HClin IPA) responsible for supersaturation favored formation of Form Acrystals and that a slower addition rate resulted in a larger medianparticle size and a lower span to the PSD.

TABLE 7 HCL IPA Solution Dosing Profiles Profile HCl IPA solutionaddition Addition Profile (i) first 10% added over approximately 15minutes 1 (AP#1) (ii) next 30% added over approximately 15 minutes (iii)remainder added over approximately 15 minutes Addition Profile (i) first10% added over approximately 90 minutes 2 (AP#2) (ii) next 30% addedover approximately 45 minutes (iii) remainder added over approximately45 minutes Addition Profile (i) first 10% added over approximately 10minutes 3 (AP#3) (ii) next 30% added over approximately 10 minutes (iii)remainder added over approximately 10 minutes Addition Profile (i) first10% added over approximately 15 minutes 4 (AP#4) (ii) next 30% addedover approximately 15 minutes (iii) remainder added over approximately15 minutes Addition Profile (i) first 10% added over approximately 20minutes 5 (AP#5) (ii) next 30% added over approximately 20 minutes (iii)remainder added over approximately 20 minutes Addition Profile (i) first10% added over approximately 30 minutes 6 (AP#6) (ii) next 30% addedover approximately 30 minutes (iii) remainder added over approximately30 minutes

TABLE 8 Particle Size Distribution Parameters for Dosing Profiles D(4,3) D10 D50 D90 Profile (μm) (μm) (μm) (μm) Addition Profile 1 109.5074.66 105.41 149.78 Addition Profile 2 170.79 114.16 164.31 236.27Addition Profile 3 149.43 55.23 131.21 273.25 Addition Profile 4 185.8079.73 167.51 323.92 Addition Profile 5 209.45 103.82 199.11 335.44Addition Profile 6 222.06 129.01 209.38 334.41

Modulation by Temperature

The (S)-(−)-TPMA freebase containing solution (e.g. solution of CompoundF in Scheme 4) was reactively-recrystallized as a crystalline form ofthe (S)-(−)-TPMA HCl salt by addition of an HCl in isopropanol (IPA) attwo different temperatures, 25° C. and 40° C. Table 9 provides variousPSD parameters of the measured PSD data at these two temperatures.

It was discovered that increasing temperature increased the median andmean particle size of the Form A crystals of (S)-(−)-TPMA HCl butincreased temperature also increased the span of the PSD.

TABLE 9 Particle Size Distribution Parameters for Various TemperaturesD(4, 3) D10 D50 D90 Temperature (μm) (μm) (μm) (μm) 40° C. 180 86 164302 25° C. 109 65 102 167

Modulation by Freebase Concentration

The (S)-(−)-TPMA freebase containing solution (e.g. solution of CompoundF in Scheme 4) was reactively-recrystallized as a crystalline form ofthe (S)-(−)-TPMA HCl salt by addition of an HCl in isopropanol (IPA)from three different starting concentrations of (S)-(−)-TPMA freebase,10.8%, 13.0% and 15.2%. Table 10 provides various PSD parameters of themeasured PSD data presented in FIGS. 8A-8C; where FIG. 8A presents PSDdata for a 15.2% (S)-(−)-TPMA freebase concentration, FIG. 8B presentsPSD data for a 13.0% (S)-(−)-TPMA freebase concentration, and FIG. 8Cpresents PSD data for a 10.8% (S)-(−)-TPMA freebase concentration.

It was discovered that increasing starting (S)-(−)-TPMA freebaseconcentration decreased both the median particle size and the PSD spanand that decreasing the starting (S)-(−)-TPMA freebase concentrationincreased the both the median particle size and the PSD span.

TABLE 10 Particle Size Distribution Parameters for Various FreebaseConcentrations Freebase Concentration D(4, 3) D10 D50 D90 (weight %)(μm) (μm) (μm) (μm) 15.2% 104 66 99 148 13.0% 109 65 102 167 10.8% 13455 124 228

Modulation by Water Content

The (S)-(−)-TPMA freebase containing solution (e.g. solution of CompoundF in Scheme 4) was reactively-recrystallized as a crystalline form ofthe (S)-(−)-TPMA HCl salt by addition of an HCl in isopropanol (IPA)from solutions of (S)-(−)-TPMA freebase with different water content(i.e. pre-nucleation water content), ranging from 2%-5.5%. Table 11provides various PSD parameters of the measured PSD data for theindicated water content.

It was discovered that increased water content generally resulted inincreased median particle size but decreased PSD span.

TABLE 11 Particle Size Distribution Parameters for Various WaterContents Water Content D(4, 3) D10 D50 D90 (before nucleation) (μm) (μm)(μm) (μm)   2% 189.0 120.8 179.6 268.7 2.5% 154.4 77.5 140.4 249.3   3%160.6 97.2 148.4 236.7 3.5% 158.4 100.3 150.0 225.5   4% 201.1 116.8192.3 294.6   5% 216.8 115.1 204.9 332.6   5% 191.9 105.9 173.9 297.95.5% 220.7 141.4 211.3 309.0

Modulation by Reaction Process

The reactive-recrystallization was carried out by two different process,(i) Process 1 employing a Plug Flow Reactor (PFR) process withultrasound applied to the reaction mixture during nucleation (e.g.during Step 4b of Scheme 4); and (ii) Process 2 a multi-stage mixedsuspension and mixed product removal (MSMPR) process.

The chemistry, e.g., chemicals, concentrations, and stoichiometry, usedin the reactive-recrystallization under Process 1 and Process 2, weresubstantially similar to that of Example 1A where Process 1 and Process2 starting with the (S)-(−)-TPMA free base solution (Compound F) ofScheme 4 in Example 1A of various concentrations.

Reactive-recrystallization under Process 1 was conducted as follows. The(S)-(−)-TPMA free base solution and the HCl/IPA solution were pumped,using peristaltic pumps, as separate feed streams into a tubingcrystallizer through a Tee mixer, at a controlled temperature (e.g., 40°C.) and residence time, to perform Step 4b of Scheme 4. Thecrystallization occurred as the process stream flowed through the tubingafter contact at the Tee. A N₂ injection system was integrated into bothfeed streams to enable periodic introduction of gas. The outputsolution, post mixer Tee, was passed through a tubular coil (⅛″ PFAtubing) of predetermined length depending on the desired residence time.For a residence time of about 2.5 minutes a coil length of 3.5 m wasused, and for a residence time of about 5 minutes a coil length of 7 mwas used. The temperature control for the coil was achieved using awater bath in which the Tee, approximately 10 cm of each of the inputstream tubes, and the coil were immersed, and sonication was achieved bysonication of the water bath during process flow.

Reactive-recrystallization under Process 2 was conducted as follows. Themulti-sage MSMPR process employed three stages with process streamscontinually pumping starting materials into a first reaction vessel(first stage crystallizer), continually pumping products out of thefirst reaction vessel into a second reaction vessel (second stagecrystallizer), continually pumping products out of the second reactionvessel into a third reaction vessel (third stage crystallizer) andcontinually pumping products out of the third reaction vessel to aproduct receiving vessel. The operation volume and reaction conditionswere kept steady state during the process and each reaction vessel wasstirred.

A starting (S)-(−)-TPMA free base isopropanol solution and 13% of theHCl isopropanol solution were pumped into the first stage with set flowrates to control the residence time and the ratio of (S)-(−)-TPMA freebase to HCl for each stage. The suspension from the first stagecrystallizer was transferred to the second stage crystallizer and 37% ofthe HCl isopropanol solution was pumped to the second stagecrystallizer. The suspension from the second stage crystallizer wastransferred to the third stage crystallizer and the reminder (50%) ofthe HCl isopropanol solution was pumped to the third stage crystallizer.Pumping was performed with peristaltic pumps. The various flow and otherconditions for each stage are summarized in Table 12.

TABLE 12 MSMPR Stage Conditions and Parameters STAGE 1 Average volume(mL) 65.00 Tau 1 (min) 10.00 Overall flow rate in Stage 1 (mL/min) 6.50Slug volume (mL) 10.00 Slug interval (min) 1.54 Feed flow rate (mL/Min)6.12 HCL in IPA flow rate (mL/min) 0.38 Operating temperature (° C.) 40Agitation rate, reaction vessel stirring, (rpm) 300 STAGE 1 Averagevolume (mL) 75.8 Tau 1 (min) 10.00 Overall flow rate in Stage 1 (mL/min)7.58 Slug volume (mL) 11.66 Slug interval (min) 1.54 HCL in IPA flowrate (mL/min) 1.08 Operating temperature (° C.) 40 Agitation rate,reaction vessel stirring, (rpm) 300 STAGE 1 Average volume (mL) 90.3 Tau1 (min) 10.00 Overall flow rate in Stage 1 (mL/min) 9.03 Slug volume(mL) 13.89 Slug interval (min) 1.54 HCL in IPA flow rate (mL/min) 1.45Operating temperature (° C.) 40 Agitation rate, reaction vesselstirring, (rpm) 300

Table 13 provides various PSD parameters of the measured PSD datapresented in FIG. 9A; and FIGS. 9B and 9C present SEM images of(S)-(−)-TPMA HCl of crystalline Form A obtained, respectively, byProcess 2 and Process 1.

It was discovered that sonication during the step of supersaturationprovided a PSD with a small median particle size and an acceptable PSDspan. On addition, it was discovered that sonication during the step ofsupersaturation favors primary nucleation of the block-like crystal form(Form A) of (S)-(−)-TPMA HCl, and facilitates avoiding the needle form(Form B).

TABLE 13 Particle Size Distribution Parameters for Various ReactionProcesses D(4, 3) D10 D50 D90 Reaction Process (μm) (μm) (μm) (μm)Process 1 (PRF with ultra-sonication) 21.9 11.4 20.3 34.8 Process 2(multi-stage MSMPR) 210.6 77.0 190.2 377.1

In various embodiments, crystalline forms of the present inventions haveseveral advantageous physical properties. For example,(S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanaminehydrochloride polymorph Form A crystalline form is substantiallynon-hygroscopic, in various embodiments exhibiting less than about a0.2%, and preferably less than about 0.1%, maximum mass change in watersorption isotherms, at 25° C. scanned over 0 to 90% relative humidity,as measured by dynamic vapor sorption (DVS) (see, for example, FIG. 5).

It is to be understood that various embodiments of the presentinventions provide crystalline(S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanaminehydrochloride of polymorph Form A, in high chiral purity and highchemical purity.

In various embodiments the present inventions provide substantiallyenantiomerically pure crystalline forms of(S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanaminehydrochloride of polymorph Form A. For example, in various embodiments,the present inventions provide crystalline forms of(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanaminehydrochloride that contain greater than about 90%(S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanaminehydrochloride and less than about 10% of(R)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanaminehydrochloride, greater than about 95%(S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanaminehydrochloride and less than about 5% of(R)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanaminehydrochloride, greater than about 97%(S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanaminehydrochloride and less than about 3% of(R)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanaminehydrochloride, greater than about 99%(S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanaminehydrochloride and less than about 1% of(R)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanaminehydrochloride, greater than about 99.5%(S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanaminehydrochloride and less than about 0.5% of(R)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanaminehydrochloride, greater than about 99.7%(S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanaminehydrochloride and less than about 0.3% of(R)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanaminehydrochloride, or greater than about 99.9%(S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanaminehydrochloride and less than about 0.1% of(R)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanaminehydrochloride.

In various embodiments the present inventions provide substantiallychemically pure crystalline forms of(S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanaminehydrochloride of polymorph Form A. For example, in various embodiments,the present inventions provide crystalline(S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanaminehydrochloride of polymorph Form A that has a greater than about 80%chemical purity, greater than about 90% chemical purity, greater thanabout 95% chemical purity, greater than about 97% chemical purity,greater than about 99% chemical purity, greater than about 99.5%chemical purity, greater than about 99.7% chemical purity, or greaterthan about 99.9% chemical purity. In various embodiments, provided iscrystalline(S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanaminehydrochloride of polymorph Form A that has less than about 8000 ppmresidual solvents, less than about 6000 ppm residual solvents, less thanabout 4000 ppm residual solvents, less than about 2000 ppm residualsolvents, less than about 1000 ppm residual solvents, less than about800 ppm residual solvents, or less than about 500 ppm residual solvents.

In various aspects, the present inventions provide formulations andcompositions comprising (S)-TPMA HCl, and/or crystalline forms thereof,and one or more pharmaceutically acceptable excipient, carrier,adjuvant, or vehicle.

In various embodiments, the compositions are formulated with one or morepharmaceutically acceptable excipients in accordance with known andestablished practice. Thus, in various embodiments the composition areformulated as, for example, a liquid, powder, elixir, injectablesolution, or suspension. Formulations for oral use are preferred and maybe provided, for instance, as tablets, caplets, or capsules, wherein thepharmacologically active ingredients are mixed with an inert soliddiluent. Tablets may also include granulating and disintegrating agents,and may be coated or uncoated. Formulations for topical use may beprovided, for example as topical solutions, lotions, creams, ointments,gels, foams, patches, powders, solids, sponges, tapes, vapors, pastes ortinctures.

In various embodiments, provided herein are compositions comprising(S)-TPMA, or a pharmaceutically acceptable salt thereof, and one or morepharmaceutically acceptable excipient, carrier, adjuvant, or vehicle,where the amount of (S)-TPMA is between about 10 mg and about 120 mg ona free base basis. In some embodiments, the amount of (S)-TPMA isbetween about 30 mg and about 100 mg on a free base basis. In someembodiments, the amount of (S)-TPMA is about 30 mg, about 40 mg, about50 mg, about 60 mg, about 70 mg, about 75 mg, about 80 mg, about 90 mg,or about 100 mg, on a free base basis. In some embodiments, the amountof (S)-TPMA is about 30 mg on a free base basis. In some embodiments,the amount of (S)-TPMA is about 50 mg on a free base basis. In someembodiments, the amount of (S)-TPMA is about 75 mg on a free base basis.In some embodiments, the amount of (S)-TPMA is about 100 mg on a freebase basis.

In various embodiments, the present inventions comprise compositionscomprising (S)-TPMA HCl and one or more pharmaceutically acceptableexcipient, carrier, adjuvant, or vehicle, where the amount of (S)-TPMAHCl is between about 30 mg and about 120 mg, and in various embodimentspreferably between about 30 mg and about 90 mg.

In various embodiments, provided herein are compositions comprising(S)-TPMA HCl, and one or more pharmaceutically acceptable excipient,carrier, adjuvant, or vehicle, where the amount of (S)-TPMA HCl isbetween about 10 mg and about 120 mg on a free base basis. In someembodiments, the amount of (S)-TPMA HCl is between about 30 mg and about100 mg on a free base basis. In some embodiments, the amount of (S)-TPMAHCl is about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg,about 75 mg, about 80 mg, about 90 mg, or about 100 mg, on a free basebasis. In some embodiments, the amount of (S)-TPMA HCl is about 30 mg ona free base basis. In some embodiments, the amount of (S)-TPMA HCl isabout 50 mg on a free base basis. In some embodiments, the amount of(S)-TPMA HCl is about 75 mg on a free base basis. In some embodiments,the amount of (S)-TPMA HCl is about 100 mg on a free base basis

In various embodiments, compositions comprising (S)-TPMA HCl formulatedas a solid oral dosage form. It is to be understood that the totalamount of a composition comprising (S)-TPMA HCl need not be provided ina single dosage unit forms, e.g. a single tablet, capsule, etc. Invarious embodiments, it is preferred that the compositions be providedin dosage unit forms such that, for example, the administration of twoof the dosage unit forms will result in administration of the desiredamount of (S)-TPMA HCl.

Pharmaceutical compositions containing the active ingredient ((S)-TPMAHCl and crystalline forms thereof) may be in any form suitable for theintended method of administration. For example, tablets, troches,lozenges, aqueous or oil suspensions, dispersible powders or granules,emulsions, hard or soft capsules, syrups or elixirs are suitable formsfor oral administration. Compositions intended for oral use can containone or more excipients, for example, sweetening agents, flavoringagents, coloring agents and preserving agents, in order to provide apalatable preparation.

In various embodiments, a composition of the inventions is formulatedfor oral administration to a subject; and in various preferredembodiments the compositions are provided in a solid oral dosage form.In various embodiments, the solid oral dosage form comprises a tablet.

In various embodiments, tablets containing the active ingredient inadmixture with non-toxic pharmaceutically acceptable excipients, whichare suitable for manufacture of tablets, are provided. These excipientsmay be, for example, inert diluents, such as microcrystalline cellulose,mannitol, calcium or sodium carbonate, lactose, lactose monohydrate,croscarmellose sodium, povidone, calcium or sodium phosphate;granulating and disintegrating agents, such as maize starch, or alginicacid; binding agents, such as cellulose, microcrystalline cellulose,starch, gelatin or acacia; disintegrating agents such as crospovidone,croscarmellose sodium or sodium starch glycolate, and lubricatingagents, such as magnesium stearate, stearic acid or talc. Tablets may beuncoated or may be coated by known techniques.

The preparation of tablets almost universally requires the presence ofexcipients in the formulations to facilitate handling, enhance thephysical appearance, improve stability and aid in the delivery of thedrug to the bloodstream after administration. These supposedly inertingredients, as well as the production methods employed, often influencethe absorption or bioavailability of the drug substances. Therefore,care must be taken in the selection and evaluation of additives andpreparation methods to ensure that the drug-delivery goals andtherapeutic efficacy of the active ingredient will not be diminished. Adrug substance's solubility and other physicochemical characteristicsinfluence its physiological availability from a solid dosage form.Important physicochemical characteristics include its particle size,whether it is amorphous or crystalline, whether it is solvated ornonsolvated and its polymorphic form. Even when otherwise clinicallyeffective formulations are obtained, variations among dosage units of agiven batch, as well as batch-to-batch differences, can result inpharmacologically unacceptable outcomes.

In various embodiments, provided are formulations comprising (S)-TPMA,or a pharmaceutically acceptable salt thereof, in the range of betweenabout 2 to about 80% w/w, on a free base basis. In various embodiments,provided are formulations comprising (S)-TPMA, or a pharmaceuticallyacceptable salt thereof, in the range of between about 5 to about 75%w/w, on a free base basis. In various embodiments, provided areformulations comprising (S)-TPMA, or a pharmaceutically acceptable saltthereof, in the range of between about 40 to about 80% w/w, on a freebase basis. In various embodiments, provided are formulations comprising(S)-TPMA, or a pharmaceutically acceptable salt thereof, in the range ofbetween about 50 to about 80% w/w, on a free base basis. In variousembodiments, provided are formulations comprising (S)-TPMA, or apharmaceutically acceptable salt thereof, in the range of between about60 to about 80% w/w, on a free base basis. In some embodiments, theamount is about 70% w/w.

In various embodiments, provided are formulations comprising (S)-TPMA,or a pharmaceutically acceptable salt thereof, in the amount of about40, about 45, about 50, about 55, about 60, about 65, about 70, about75, or about 80% w/w, on a free base basis. In various embodiments,provided are formulations comprising (S)-TPMA, or a pharmaceuticallyacceptable salt thereof, in the amount of about 10% w/w on a free basebasis. In various embodiments, provided are formulations comprising(S)-TPMA, or a pharmaceutically acceptable salt thereof, in the amountof about 20% w/w on a free base basis. In various embodiments, providedare formulations comprising (S)-TPMA, or a pharmaceutically acceptablesalt thereof, in the amount of about 40% w/w on a free base basis. Invarious embodiments, provided are formulations comprising (S)-TPMA, or apharmaceutically acceptable salt thereof, in the amount of about 50% w/won a free base basis. In various embodiments, provided are formulationscomprising (S)-TPMA, or a pharmaceutically acceptable salt thereof, inthe amount of about 60% w/w on a free base basis. In variousembodiments, provided are formulations comprising (S)-TPMA, or apharmaceutically acceptable salt thereof, in the amount of about 70% w/won a free base basis.

In various embodiments, provided are tablet formulations comprising(S)-TPMA hydrochloride in the range of between about 2.4% w/w to about60% w/w, and in various preferred embodiments in the range of betweenabout 10% w/w to about 40% w/w.

In various embodiments, provided are formulations comprising (S)-TPMAHCl in the range of between about 2 to about 80% w/w, on a free basebasis. In various embodiments, provided are formulations comprising(S)-TPMA HCl in the range of between about 5 to about 75% w/w, on a freebase basis. In various embodiments, provided are formulations comprising(S)-TPMA HCl in the range of between about 5 to about 50% w/w, on a freebase basis. In various embodiments, provided are formulations comprising(S)-TPMA HCl in the range of between about 5 to about 40% w/w, on a freebase basis. In various embodiments, provided are formulations comprising(S)-TPMA HCl in the range of between about 10 to about 40% w/w, on afree base basis. In various embodiments, provided are formulationscomprising (S)-TPMA HCl in the range of between about 10 to about 40%w/w, on a free base basis.

In various embodiments, provided are formulations comprising (S)-TPMAHCl in the amount of about 10% w/w on a free base basis. In variousembodiments, provided are formulations comprising (S)-TPMA HCl in theamount of about 20% w/w on a free base basis. In various embodiments,provided are formulations comprising (S)-TPMA HCl in the amount of about25% w/w on a free base basis. In various embodiments, provided areformulations comprising (S)-TPMA HCl in the amount of about 30% w/w on afree base basis. In various embodiments, provided are formulationscomprising (S)-TPMA HCl in the amount of about 35% w/w on a free basebasis.

In some embodiments, the formulation is a tablet. In some embodiments,the formulation further comprises a filler. In some embodiments, theformulation further comprises a disintegrant. In some embodiments, theformulation further comprises a lubricant. In some embodiments, theformulation further comprises a coating.

In various embodiments, tablets provided herein comprise a corecomprising: (i) (S)-TPMA, or a pharmaceutically acceptable salt thereof,in the range of between about 10 to about 40% w/w, on a free base basis;(ii) filler; (iii) disintegrant; (iv) lubricant; and optionally (v)glidant. In some embodiments, tablet comprises a coating comprising: (i)a matrix as a polymer coating system; and optionally one or more of:(ii) opacifier and colorant, (iii) polishing agent, and (iv) and othercolorants to provide various tablet colors for, e.g., market need.

In some embodiments, a pharmaceutically acceptable salt of (S)-TPMA is(S)-TPMA HCl. In some embodiments, (S)-TPMA HCl is Form A or Form B. Insome embodiments, provided herein is a formulation comprising(S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine, or apharmaceutically acceptable salt thereof, in the range of between about2 to about 80% w/w, on a free base basis, wherein, the(S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanaminehydrochloride is Form A or Form B.

In some embodiments, the filler is microcrystalline cellulose, mannitol,or a combination thereof. In some embodiments, the disintegrant issodium starch glycolate. In some embodiments, the lubricant is magnesiumstearate. In some embodiments, the glidant is colloidal silicon dioxide.In some embodiments, the polymer coating system is (hydroxypropyl)methyl cellulose (HPMC)/hydroxypropylcellulose (HPC). In someembodiments, the opacifier and colorant is titanium dioxide. In someembodiments, the polishing agent is carnauba wax.

In various embodiments, tablets of the present inventions comprise: (a)a core comprising: (i) (S)-TPMA hydrochloride in the range of betweenabout 2.4% w/w to about 60% w/w, and in various preferred embodiments inthe range of between about 10% w/w to about 40% w/w; (ii)microcrystalline cellulose and mannitol as filler; (iii) sodium starchglycolate as disintegrant; (iv) magnesium stearate as lubricant; andoptionally (v) colloidal silicon dioxide (if needed) as glidant; and (b)a coating comprising: (i) a (hydroxypropyl) methyl cellulose(HPMC)/hydroxypropylcellulose (HPC) matrix as a polymer coating system;and optionally one or more of: (ii) titanium dioxide as opacifier andcolorant, (iii) carnauba wax as polishing agent, and (iv) and othercolorants to provide various tablet colors for, e.g., market need. Invarious preferred embodiments, the concentration of each ingredient isselected based on powder flowability, tabletability and tablet stabilityafter storage at accelerated and long-term conditions.

In some formulations, micro-cracking in tablets was observed. This wasaddressed by changing the compression process, e.g., changing thecompression location within the die. The ejection force can be decreasedby eliminating colloidal silicon dioxide (Cabosil) from the formulationand increasing microcrystalline cellulose (MCC):mannitol ratio. In someembodiments, the formulation does not include colloidal silicon dioxideand the MCC:mannitol ratio is approximately 5:1. It has been shown thatbinary mixtures (1:1) of API with Opadry 03F110000 (green), Opadry03F180011 (white), Opadry II 85F18422 (white), copovidone, crospovidone,and sodium stearyl fumarate, are stable when stored in closed glassvials for 6 or 9 months at 40° C./75% RH. Based on binary excipientcompatibility data, these excipients can potentially be used for tabletformulations. Binary mixture of API (1:1) with colloidal silicon dioxideare not stable even after 2 weeks at 40° C./75% RH.

In some embodiments, the formulation does not include colloidal silicondioxide (e.g., (S)-TPMA hydrochloride granule, microcrystallinecellulose, mannitol, sodium starch glycolate, and magnesium stearate).In some embodiments, the formulation does not include mannitol (e.g.,(S)-TPMA hydrochloride granule, microcrystalline cellulose, sodiumstarch glycolate, colloidal silicon dioxide and magnesium stearate). Insome embodiments, the formulation does not include mannitol andcolloidal silicon dioxide (e.g., (S)-TPMA hydrochloride granule,microcrystalline cellulose, sodium starch glycolate, and magnesiumstearate).

In some embodiments, the (S)-TPMA hydrochloride is Form A or Form B. Insome embodiments, the (S)-TPMA hydrochloride is Form A. In someembodiments, the (S)-TPMA hydrochloride is Form B.

In various aspects, provided are methods of manufacture for a solid oraldosage form comprising (S)-TPMA. In various embodiments, provided aremethods for formation of a tablet by, for example, direct compression ordry granulation.

Example 3: Tablet Formulations and Manufacture

(S)-TPMA hydrochloride tablets were manufactured by using a dry process.Direct compression was used for 25 mg tablets, and dry granulationfollowed by compression was used for dose strengths of 50, 75 and 100mg. In some embodiments, the API is milled prior to blending withexcipients. The composition of the 25 mg strength tablets is summarizedin Table 14, and the compositions of the 50, 75 and 100 mg strengthtablets are summarized in Table 15A, Table 15B, Table 15C, and Table15D; including the core tablet and the coating applied to the core. Itis to be understood that although yellow is listed as the color for thecoated tablet in these tables, the tablet color may be changed based,e.g., on market need, with the polymer coating system remainingunchanged. For the dosage strength of 25 mg based on the amount of freebase, i.e. (S)-TPMA, in the compound (S)-TPMA hydrochloride,microcrystalline cellulose, mannitol, and sodium starch glycolate weresieved individually through a #30 mesh screen and charged into a lowshear blender. The mixture was blended for up to 500 revolutions. Insome examples, the mixture was blended for up to 300 revolutions.Magnesium stearate was sieved though a #60 mesh screen, charged into theblender and the mixture blended for an additional 75 revolutions. Theblend was then compressed into tablets with a target tablet weight of300 mg. The tablets were then coated with Opadry 20A120006 Yellow,Opadry 20A18407 White or Opadry 20A110008 Green (hydroxypropylmethylcellulose/hydroxypropyl cellulose), and carnauba wax was applied ontothe tablets after drying.

For the dose strengths (based on the amount of free base) greater than25 mg, intra-granular blend included (S)-TPMA hydrochloride,microcrystalline cellulose, and sodium starch glycolate were sievedindividually through a #30 mesh screen and charged into a low shearblender. The mixture was blended for up to 500 revolutions. In someexamples, the mixture was blended for up to 300 revolutions. In someexamples, the mixture was blended for up to 250 revolutions, Magnesiumstearate was sieved though a #60 mesh screen, charged into the blenderand the mixture blended for additional 75 revolutions. Theintra-granular blend was then dry granulated into ribbons, and milledinto granules.

After dry granulation, depending on the target tablet strength,different amount of granules were used and blended with theextra-granular excipients before compression. The final blend included(S)-TPMA hydrochloride granule, microcrystalline cellulose, mannitol,sodium starch glycolate, colloidal silicon dioxide (for 75 and 100 mgonly) and magnesium stearate. In some examples, the final blend does notinclude colloidal silicon dioxide (e.g., (S)-TPMA hydrochloride granule,microcrystalline cellulose, mannitol, sodium starch glycolate, andmagnesium stearate). In some embodiments, the final blend does notinclude mannitol (e.g., (S)-TPMA hydrochloride granule, microcrystallinecellulose, sodium starch glycolate, colloidal silicon dioxide andmagnesium stearate). In some examples, the final blend does not includemannitol and colloidal silicon dioxide (e.g., (S)-TPMA hydrochloridegranule, microcrystalline cellulose, sodium starch glycolate, andmagnesium stearate). The strengths of 25 mg, 50 mg, 75 mg, and 100 mg of(S)-TPMA hydrochloride on a free base basis can be prepared from thefinal blend with or without colloidal silicon dioxide, or from the finalblend with or without mannitol. Microcrystalline cellulose, mannitol,sodium starch glycolate and colloidal silicon dioxide were sievedindividually or co-sieved with microcrystalline cellulose (for colloidalsilicon dioxide only) through a #30 mesh screen and charged into a lowshear blender with (S)-TPMA hydrochloride granule for blending. Themixture was blended for 250 revolutions. Extra-granular magnesiumstearate was sieved through a #60 mesh screen and charged into theblender. The mixture was then blended for 75 revolutions and thencompressed into tablets with target tablet weight of 300 mg. The tabletswere then coated with Opadry 20A120006 Yellow, Opadry 20A18407 White orOpadry 20A110008 Green (hydroxypropylmethyl cellulose/hydroxypropylcellulose), and carnauba wax was applied onto the tablets after drying.

For the dose strengths (based on the amount of free base) greater than25 mg, intra-granular blend included (S)-TPMA hydrochloride,microcrystalline cellulose, and sodium starch glycolate were sievedindividually through a #30 mesh screen and charged into a low shearblender. In some examples, (S)-TPMA hydrochloride was milled prior togranulation. The mixture was blended for 300 revolutions. Magnesiumstearate was sieved though a #60 mesh screen, charged into the blenderand the mixture blended for additional 75 revolutions. Theintra-granular blend was then dry granulated into ribbons and milledinto granules. After dry granulation, the granules and theextra-granular excipients were blended before compression. The finalblend included (S)-TPMA hydrochloride granule, microcrystallinecellulose, sodium starch glycolate and magnesium stearate. The 50 mg and75 mg also contained mannitol as extra-granular excipient.Microcrystalline cellulose, mannitol, sodium starch glycolate weresieved through a #30 mesh screen and charged into a low shear blenderwith (S)-TPMA hydrochloride granule for blending. The mixture wasblended for 300 revolutions. Extra-granular magnesium stearate wassieved through a #60 mesh screen and charged into the blender. Themixture was then blended for 75 revolutions and then compressed intotablets with target tablet weight of 300 mg. The tablets were thencoated with Opadry 20A120006 Yellow, Opadry 20A18407 White or Opadry20A110008 Green (hydroxypropylmethyl cellulose/hydroxypropyl cellulose),and carnauba wax was applied onto the tablets after drying.

For all four dose strengths of 25 mg, 50 mg, 75 mg, and 100 mg a commonblend can be used and made into tablets at 75 mg, 150 mg, 225 mg, and300 mg weight respectively. For example, intra-granular blend included(S)-TPMA hydrochloride, microcrystalline cellulose, and sodium starchglycolate sieved individually through a #30 mesh screen and charged intoa low shear blender. The mixture was blended for 300 revolutions.Magnesium stearate was sieved though a #60 mesh screen, charged into theblender and the mixture blended for additional 75 revolutions. Theintra-granular blend was then dry granulated into ribbons and milledinto granules. After dry granulation, the granules and theextra-granular excipients were blended before compression. The finalblend included (S)-TPMA hydrochloride granule, microcrystallinecellulose, sodium starch glycolate and magnesium stearate.Microcrystalline cellulose and sodium starch glycolate were sievedthrough a #30 mesh screen and charged into a low shear blender with(S)-TPMA hydrochloride granule for blending. The mixture was blended for300 revolutions. Extra-granular magnesium stearate was sieved through a#60 mesh screen and charged into the blender. The mixture was thenblended for 75 revolutions. The blend can be compressed into tablets of75 mg, 150 mg, 225 mg, and 300 mg for 25 mg, 50 mg, 75 mg, and 100 mgtablet strengths, respectively. In other words, different strengths of(S)-TPMA hydrochloride can be prepared from a single blend having thesame components by taking the corresponding amounts of the blend andcompressing them into tablets. See e.g., Table 15C and Table 15D.

TABLE 14 Example Compositions of (S)-TPMA hydrochloride Tablets, DoseStrength 25 mg Composition mg/tablet Ingredient Function (% w/w) CoreTablet (S)-TPMA API 30.00 (10.00) hydrochloride Microcrystalline Filler173.0 (57.67) Cellulose Mannitol Filler 86.50 (28.83) Sodium StarchGlycolate Disintegrant 9.000 (3.00) Magnesium Stearate Lubricant 1.500(0.50) Total 300.0 (100.0) Coating Core Tablet Core Tablet 300.0 (96.7)Opadry 20A120006 Polymer Coating System 10.30 (3.32) Yellow, Opadry20A18407 White, or Opadry 20A110008 Green (HPMC/HPC) Carnauba waxPolishing agent 0.012 (0.00387) Total 310.3 (100.0)

TABLE 15A Example Compositions of (S)-TPMA hydrochloride Tablets, DoseStrengths 50, 75 and 100 mg Dose Strength (mg) 50 75 100 IngredientFunction Composition Core Tablet, Intra-Granular (% w/w) (S)-TPMA API70.00 hydrochloride Microcrystalline Filler 27.80 Cellulose SodiumStarch Disintegrant 2.00 Glycolate Magnesium Stearate Lubricant 0.20Total 100 Core Tablet mg/tablet (% w/w) (S)-TPMA API 85.71 128.6 171.4hydrochloride Granules (28.57) (42.86) (57.14) Microcrystalline Filler137.9 108.8 90.24 Cellulose (45.97) (36.27) (30.08) Mannitol Filler68.93 54.39 30.08 (22.98) (18.13) (10.03) Sodium Starch Disintegrant6.000 6.000 6.000 Glycolate (2.00) (2.00) (2.00) Colloidal siliconGlidant n/a 0.7500 0.7500 dioxide (0.25) (0.25) Magnesium StearateLubricant 1.500 1.500 1.500 (0.500) (0.500) (0.500) Total 300.0 300.0300.0 (100) (100) (100) Coating Core Tablet Core 300.0 300.0 300.0Tablet (96.7) (96.7) (96.7) Opadry 20A120006 Polymer 10.30 10.30 10.30Yellow, Opadry Coating (3.32) (3.32) (3.32) 20A18407 White, System orOpadry 20A110008 Green (HPMC/HPC) Carnauba wax Polishing 0.012 0.0120.012 agent (0.00387) (0.00387) (0.00387) Total 310.3 310.3 310.3 (100)(100) (100) Note, a similar batch was made with colloidal silicondioxide (cabosil) for 50 mg strength as in Table 15A. Also batches of 75and 100 mg strengths were made without cabosil as in Table 15A.

TABLE 15B Additional Example Compositions of (S)-TPMA hydrochlorideTablets, Dose Strengths 50, 75 and 100 mg Dose Strength (mg) 50 75 100Ingredient Function Composition Core Tablet, Intra-Granular (% w/w)(S)-TPMA API 70.00 hydrochloride Microcrystalline Filler 27.80 CelluloseSodium Starch Disintegrant 2.00 Glycolate Magnesium Stearate Lubricant0.2 Total 100 Core Tablet mg/tablet (% w/w) (S)-TPMA API 85.71 128.6171.4 hydrochloride (28.57) (42.86) (57.14) Granules MicrocrystallineFiller 155.1 137.4 121.1 Cellulose (51.70) (45.81) (40.36) MannitolFiller 51.70 26.50 n/a (17.23) (8.83) Sodium Starch Disintegrant 6.0006.000 6.000 Glycolate (2.00) (2.00) (2.00) Magnesium Stearate Lubricant1.500 1.500 1.500 (0.50) (0.50) (0.50) Total 300.0 300.0 300.0 (100)(100) (100) Coating Core Tablet Core Tablet 300.0 300.0 300.0 (96.7)(96.7) (96.7) Opadry 20A120006 Polymer 10.30 10.30 10.30 Yellow, OpadryCoating (3.32) (3.32) (3.32) 20A18407 White, System or Opadry 20A110008Green (HPMC/HPC) Carnauba wax Polishing 0.012 0.012 0.012 agent(0.00387) (0.00387) (0.00387) Total 310.3 310.3 310.3 (100) (100) (100)

TABLE 15C Common blend formulation Ingredient Function % w/w CommonBlend, Intra Granular (S)-TPMA hydrochloride API 70.00 MicrocrystallineCellulose Filler 27.80 Sodium Starch Glycolate Disintegrant 2.00Magnesium Stearate Lubricant 0.20 Total 100 Common Blend for Compression(S)-TPMA hydrochloride API 57.14 Granules Microcrystalline CelluloseFiller 40.36 Sodium Starch Glycolate Disintegrant 2.00 MagnesiumStearate Lubricant 0.50 Total 100

TABLE 15D Tablet formulation composition using common blend forcompression formulation Dose Strength (mg) 25 mg 50 mg 75 mg 100 mgIngredient Function % w/w (S)-TPMA hydrochloride API 40.00Microcrystalline Cellulose Filler 56.24 Sodium Starch GlycolateDisintegrant 3.14 Magnesium Stearate Lubricant 0.62 Total (%) 100 Total(mg/tablet) 75.0 150.0 225.0 300.0 Coating, mg (% w/w) Core Tablet CoreTablet 75.0 150.0 225.0 300.0 (96.7) (96.7) (96.7) (96.7) Opadry20A120006 Polymer Coating 2.58 5.15 7.73 10.30 Yellow, Opadry 20A18407System (3.32) (3.32) (3.32) (3.32) White, or Opadry 20A110008 Green(HPMC/HPC) Carnauba wax Polishing agent 0.003 0.006 0.009 0.012(0.00387) (0.00387) (0.00387) (0.00387) Total 77.6 155.2 232.7 310.3(100) (100) (100) (100)

The actual amount of polymer coating system is an estimate in Table 15D.The actual quantities may change when tablets of lower weights are madeand coated. Similarly, the actual amount of polishing agent is anestimate. The actual quantities may change when tablets of lower weightsare made and coated and waxed/polished.

XRPD analyses for Examples 4-8 and 12 were performed using a RigakuMiniFlex II Desktop X-Ray diffractometer using Cu radiation. The tubevoltage and amperage were set to 30 kV and 15 mA, respectively. Thescattering slit was fixed at 1.25° and the receiving slit was fixed at0.3 mm. Diffracted radiation was detected by a NaI scintillationdetector. A θ-2θ continuous scan at 1.0°/min with a step size of0.02-0.05° from 3 to 45° 2θ was used. Data were collected and analyzedusing Jade 8.5.4. Each sample was prepared for analysis by placing it ina low background, round, 0.1 mm indent sample holder.

The DSC analyses for Examples 4-8 were performed using TA InstrumentsQ100 differential scanning calorimeter. Each sample was analyzed in analuminum pan with crimped lid. Each sample was heated under a 50 mL/minnitrogen purge at a heating rate of 10° C./min, from a startingtemperature of 25° C. up to a final temperature of 200-300° C. Samplesize ranged from 1.6 to 8.0 mg.

Water content by coulometric titration analyses for Examples 4-8 wereperformed using an EM Scientific Aquastar C3000 titrator to determinewater content. Sample size ranged from 18 mg to 134 mg.

DVS moisture sorption isotherms for Examples 4-8 were generated usingthe VTI SGA-100 Symmetric Vapor Sorption Analyzer. Analysis includedpre-analysis drying at 25° C. with equilibrium criteria of 0.0000 wt %change in 5 minutes or a maximum of 180 minutes. Equilibrium criteriawere the lesser of 0.01 wt % change in 5 minutes or 180 minutes at eachRH step. Temperature was fixed at 25° C. and the relative humidity steps(25% to 95% to 25%) were in 5% increments. Analysis was repeated foreach sample in consecutive analyses (sample was not removed fromanalyzer). Sample sizes ranged from 14 mg to 73 mg.

Example 4: (S)-TPMA R-Mandelate

The crystalline form of (S)-TPMA R-mandelate was analyzed using XRPD,DSC, coulometric titration, and DVS. FIG. 11 shows the XRPD and Table 4provides a list of the peaks.

TABLE 4 (S)-TPMA R-Mandelate XRPD (FIG. 12) Peak List 2-Theta (degree)Relative height (%)  4.7 6.9  9.4 74.8 10.7 4.9 11.1 6.1 12.4 2.5 13.75.9 14.3 29.2 15.3 3.7 16.3 83.7 17.5 2.4 18.0 10.9 18.4 8.3 18.9 12.819.6 27.8 20.0 8.3 21.4 14.3 21.8 25.7 23.0 17.9 23.4 40.9 23.7 100 24.420.8 25.0 63.2 25.3 39.3 25.6 13.4 26.1 5.8 26.8 12.2 27.4 19.4 28.3 8.929.0 8.7 29.5 15 30.2 3.1 30.8 8.6 31.5 2.8 32.5 4.3 32.8 3.8 33.4 7.334.4 3.6 34.7 5.5 35.2 10.6 36.2 5.7 37.0 6.6 37.6 12.7 38.2 2.7 39.27.5 39.8 2.7 41.1 7.4 41.8 9.5 42.3 11.5 43.2 6.1 43.6 5

The DSC as shown in FIG. 12 displays an onset temperature of 127° C.with an endotherm peak at 129° C. The amount of water content asdetermined by coulometric titration was 0.03% water. The TGA is shown inFIG. 13.

Example 5: (S)-TPMA L-Tartrate

The crystalline form of (S)-TPMA L-tartrate was analyzed using XRPD,DSC, coulometric titration, and DVS. FIG. 14 shows the XRPD and Table 5provides a list of the peaks.

TABLE 5 (S)-TPMA L-tartrate XRPD (FIG. 14) Peak List 2-Theta (degree)Relative height (%)  6.3 20.1 12.7 99.0 12.9 19.6 14.3 2.4 14.7 13.716.0 26.5 17.1 23.8 17.4 27.9 18.1 14.9 19.1 100.0 19.5 9.6 20.4 6.821.3 10.2 22.2 1.8 22.9 24.7 23.4 7.9 24.6 11.0 25.0 2.4 25.5 20.6 25.841.9 26.3 43.6 26.9 3.0 27.6 3.9 27.9 13.1 28.2 10.4 28.6 1.9 29.1 2.829.7 2.7 30.7 19.1 31.1 6.0 32.0 24.7 32.5 12.4 33.6 22.7 34.4 12.4 35.22.0 36.6 5.0 36.9 8.1 37.9 10.4 38.7 12.7 39.4 10.2 40.3 12.0 40.7 3.341.5 3.7 42.5 4.5 43.0 2.5 43.5 4.4 44.1 3.0 44.4 7.6

The DSC as shown in FIG. 15 displays an onset temperature of 149° C.with an endotherm peak at 152° C. The amount of water content asdetermined by coulometric titration was 0.07% water. The DVS is shown inFIG. 16.

Example 6: (S)-TPMA D-Tartrate

The crystalline form of (S)-TPMA D-tartrate was analyzed using XRPD,DSC, coulometric titration, and DVS. Three crystalline forms wereobserved: Form DA, Form DB, and form DC. FIG. 17 shows the XRPD of FormDA; Table 6A provides a list of the peaks. FIG. 18 shows the XRPD ofForm DB; Table 6B provides a list of the peaks. FIG. 19 shows the XRPDof Form DC; Table 6C provides a list of the peaks. XRPD patterns of FormDA, DB, and DC may not represent unique pure polymorphic forms and canbe a mixture of forms.

TABLE 6A (S)-TPMA D-tartrate XRPD (FIG. 17) Peak List 2-Theta (degree)Relative height (%)  7.0 25.5 11.4 0.7 12.9 4.3 13.9 3.7 14.1 1.9 15.08.8 16.4 3.0 16.8 4.5 17.6 37.3 18.6 1.4 18.8 0.7 19.5 13.7 20.8 100.021.5 12.6 21.8 14.6 22.0 7.6 22.8 3.0 23.5 1.4 23.9 9.8 24.2 7.3 24.60.9 24.9 2.1 25.3 2.9 26.0 46.2 26.7 2.8 27.2 3.7 27.8 21.5 28.7 2.229.0 3.2 29.4 4.7 30.0 3.5 30.2 1.0 32.2 2.5 32.5 2.4 32.8 1.4 33.0 1.133.8 2.2 34.3 2.6 35.0 9.9 35.7 3.0 36.8 15.5 37.2 3.6 37.5 17.0 37.96.8 39.1 6.6 39.6 0.6 40.4 2.5 40.7 4.5 41.2 2.1 41.9 0.8 42.3 0.8 42.92.0 43.3 1.1 43.7 4.8

TABLE 6B (S)-TPMA D-tartrate XRPD (FIG. 18) Peak List 2-Theta (degree)Relative height (%)  6.9 1.3 11.6 10.7 12.8 1.1 14.0 0.3 14.9 2.4 16.31.2 16.7 1.6 17.5 8.8 18.8 2.5 19.4 3.0 20.1 4.7 20.7 44.3 21.5 2.8 21.64.3 21.9 2.0 22.5 1.6 22.8 0.8 23.4 13.9 23.8 1.7 24.1 1.1 25.0 5.6 25.96.2 27.1 1.0 27.8 2.0 28.6 0.8 29.2 20.4 29.7 5.3 32.0 5.2 33.4 10.834.3 0.4 35.3 27.8 35.8 100.0 36.1 1.6 36.7 9.5 37.4 8.3 37.9 1.3 38.40.6 38.8 3.2 39.4 0.6 41.1 0.6 42.6 0.9 43.9 5.4

TABLE 6C (S)-TPMA D-tartrate XRPD (FIG. 19) Peak List 2-Theta (degree)Relative height (%)  8.7 0.9  9.8 0.8 10.8 8.8 11.7 3.0 12.8 1.0 13.32.3 15.8 10.3 16.2 2.1 17.5 100.0 18.2 2.9 18.7 2.1 19.4 5.8 19.8 1.820.7 10.4 21.7 6.7 22.2 0.9 22.8 1.5 23.6 12.7 24.2 4.1 26.1 4.4 26.810.0 27.2 3.2 27.7 1.6 29.3 1.8 29.8 3.7 30.2 2.5 31.3 1.0 31.9 1.4 32.50.9 32.9 1.6 34.0 1.2 34.7 2.6 35.3 2.8 36.0 2.9 37.0 1.2 37.4 1.5 37.81.2 38.4 0.5 38.8 0.7 40.0 0.4 40.6 0.6 41.0 1.1 41.5 0.9 42.0 0.8 42.30.8 43.7 0.7 44.3 2.3

The DSC of Form DA as shown in FIG. 20 displays an onset temperature of168° C. with an endotherm peak at 170° C. The DSC of Form DB as shown inFIG. 21 displays an onset temperature of 107° C. with an endotherm peakat 111° C. The DSC of Form DC as shown in FIG. 22 displays an onsettemperature of 158° C. with an endotherm peak at 160° C., and an onsettemperature of 183° C. and an endotherm peak at 185° C.

The amount of water content as determined by coulometric titration was0.12% for Form DA, 0.09% for Form DB, and 0.06% for Form DC. The DVS forForm DA is shown in FIG. 23.

Example 7: (S)-TPMA Mesylate and (S)-TPMA L-Malate

The mesylate salt was observed in a polymorph study and was analyzedusing DVS. FIG. 24 shows the DVS.

The L-maleate salt was observed in a polymorph study and was analyzedusing DVS. FIG. 25 shows the DVS.

Example 8: (S)-TPMA Besylate

The crystalline form of (S)-TPMA besylate was analyzed using XRPD, DSC,coulometric titration, and DVS. Form BA was observed. FIG. 25 shows theXRPD and Table 8 provides a list of the peaks of Form BA.

TABLE 8 (S)-TPMA besylate Form BA XRPD (FIG. 25) Peak List 2-Theta(degree) Relative height (%)  6.1 79.3 12.3 14.3 13.2 5.0 14.6 2.3 16.738.4 18.5 3.6 18.8 7.1 19.0 25.9 19.5 2.2 21.9 25.4 22.4 18.5 22.8 22.423.2 9.6 23.8 2.2 24.3 8.0 24.7 100.0 26.0 10.6 26.5 3.7 27.0 13.9 27.514.6 27.8 4.3 28.6 2.2 29.2 0.8 30.1 2.5 30.8 5.0 31.0 2.7 32.2 11.632.8 2.6 33.3 10.8 33.7 2.0 34.1 2.7 34.4 2.8 35.9 2.1 36.6 6.8 37.919.0 38.6 4.3 39.3 4.9 39.6 1.7 40.4 3.1 41.5 0.8 42.1 5.2 42.8 0.7 43.51.7 43.9 11.2 44.5 5.1

The DSC as shown in FIG. 26 displays an onset temperature of 141° C.with an endotherm peak at 142° C. The amount of water content asdetermined by coulometric titration was 0.03% water. The DVS is shown inFIG. 27.

Example 9: Study of Solid State Stability

Solid samples (˜25 mg each) of (S)-TPMA HCl and (S)-TPMA besylate wereplaced in 4 mL clear glass borosilicate vials with screw caps. Sampleswere stored at 40° C./75% RH and analyzed by AR&D after 27 days storage.

Results show no change in parent peak area or impurity area percent ineither HCL or besylate salts. Refer to results in Table 9.

TABLE 9 Solid State Stability Results for HCl and Besylate Salts TimeUnknown Total Point Wt. RF Impurities Impurity 1 Impurities (days) PeakArea (mg) (counts/mg) (%) (%) (%) HCl 0 16,969,358 25.42 667,559 0 1.201.20 27 17,199,832 25.79 666,919 0 1.21 1.21 Besylate 0 10,901,819 25.15433,472 0 0.64 0.64 27 11,126,833 25.61 434,472 0 0.64 0.64Both HCl and besylate salts are stable in the solid state after 27 daysat 40° C./75% RH. Impurity 1 is:

Example 10: Study of Solubility in Aqueous Systems

Buffer preparation for simulated gastric fluid (pH 1.2, ˜0.1N HCl, 0.03MNaCl), simulated intestinal fluid (pH 6.7, 0.05M KH2PO4, ˜0.02N NaOH),and acetate buffer (pH 4.6, 0.02M sodium acetate, 0.03M acetic acid)were in accordance with USP27 [Ref 3]. Enzymes were not added to thesimulated gastric or intestinal fluids. Approximately 200 mg of selectedsalts were weighed into clear glass HPLC vials. One milliliter ofde-ionized water was added to each vial. In each case, a clear solutionresulted and pH of final solution measured. Results (Table 11a) werereported as “greater than” the concentration of the solution.

Additional solubility experiments were performed on (S)-TPMA HCl salt.Approximately 250 mg of (S)-TPMA HCl salt were weighed into clear glassHPLC vials. Approximately 900 μL of each test solvent were added to eachvial. In each case, a clear yellow solution resulted and the pH of thefinal solution was measured.

Results (Table 10a) were reported as “greater than” the concentration ofthe solution. Refer to solubility results in Table 10a and Table 10b.

TABLE 10a Apparent Solubility Values for (S)-TPMA Salts in De-IonizedWater Solubility Final solution Salt (mgA/mL)^(a) PH USP DescriptorHCl >167 5.3 Freely Soluble L-Tartrate >110 3.3 Freely SolubleBesylate >109 4.7 Freely Soluble R-Mandelate >107 6.2 Freely Soluble^(a)= solubility expressed in terms of free base.

TABLE 10b Apparent Solubility Values for (S)-TPMA HCl in Aqueous BufferSystems Final Solution Solubility USP Solvent pH (mgA/mL)^(a) DescriptorSimulated Gastric 1.28 >200 Freely Soluble Fluid (SGF) 0.05M AcetateBuffer 4.60 >200 Freely Soluble Deionized H₂O 6.20 >200 Freely SolubleSimulated Intestinal 7.70 >200 Freely Soluble Fluid (SIF) ^(a)=solubility is expressed in terms of free base. Enzymes were not added tothe stimulated gastric or intestinal fluids.

The selected salt has good solubility (i.e. >1 mgA/mL) at physiologicalpHs and conditions such as SGF (pH 1.2), SIF (pH 6.8), and acetatebuffer (pH 4.5). All salts tested (HCl, L-tartrate, besylate, andR-mandelate) are freely soluble in de-ionized water. HCl salt is freelysoluble in aqueous buffers ranging from pH 1.3 to 7.7.

Example 11: Polymorph Study of (S)-TPMA Besylate

A polymorph study was conducted on (S)-TPMA besylate. The startingmaterial used in the study was designated Form BA, with characterizationdiscussed below.

(S)-TPMA was treated as being light sensitive, with exposure to lightminimized throughout the experiments. These abbreviations are used inthis study: ACN—Acetonitrile, B/E—Birefringence/Extinction, CC—CrashCool, DCM—Dichloromethane, DSC—Differential Scanning calorimetry,EtOAc—Ethyl Acetate, EtOH—Ethanol, FE—Fast Evaporation, H2O—Water,IPA—Isopropanol, IS—Insufficient Sample, MEK—Methyl Ethyl Ketone,MeOH—Methanol, mg—Milligram, mL—Milliliter, PO—Preferred Orientation,Rotovap—Rotary Evaporation, RT—Room/ambient temperature,S/AS—Solvent/Anti-Solvent, SC—Slow Cool, SE—Slow Evaporation, Tg—GlassTransition Temperature, THF—Tetrahydrofuran, UM—Undefined Morphology,v/v—Volume by Volume, vac—Vacuum, VD—Vapor Diffusion, VT—VariableTemperature, and XRPD—X-Ray Powder Diffraction.

Approximate Solubility Determination: Aliquots of the test solvent wereadded to a weighed sample of (S)-TPMA besylate with sonication at eachaddition. Dissolution was determined by visual inspection. If the sampledissolved upon addition of the first aliquot, the solubility is reportedas “greater than or equal to”. If the sample did not dissolve, thesolubility is reported as “less than”. Actual solubilities may be higherthan reported due to slow rates of dissolution and to addition ofover-sized aliquots.

Fast Evaporation: A solution of (S)-TPMA besylate was prepared andfiltered. The sample was left open under ambient conditions forevaporation.

Slow Evaporation: A solution of (S)-TPMA besylate was prepared andfiltered. The vial containing the sample was covered with foilcontaining pinholes. The covered sample was left under ambientconditions for evaporation.

Slurries: A solution of (S)-TPMA besylate containing excess solids wasprepared and agitated at a given temperature for a given time.

Slow Cool: A saturated solution of (S)-TPMA besylate was prepared in anelevated temperature oil bath. The sample was filtered with a warmfilter into a warm vial and then returned to the oil bath. The heat wasturned off, and the sample was allowed to slowly cool to ambienttemperature. When precipitation was not observed at ambient temperature,the sample was placed in a refrigerator. After the refrigerator, sampleswere moved to a freezer.

Crash Cool: A saturated solution of (S)-TPMA besylate was prepared in anelevated temperature oil bath. The sample was filtered with a warmfilter into a vial and then plunged into a dry ice/acetone bath. Ifprecipitation did not occur, the sample was placed in a freezer.

Solvent/Anti-Solvent Crash Precipitation: A solution of (S)-TPMAbesylate was prepared, filtered, and combined with an anti-solvent. Ifprecipitation was not observed, the sample was placed in a freezer. Ifprecipitation was not achieved in the freezer, samples were evaporatedeither partially or to dryness.

Grinding Experiments: A sample of (S)-TPMA besylate was placed in anagate canister with an agate ball. In the case of solvent drop grindingexperiments, a small amount (10 μL) of solvent was added. The sample wascapped, parafilmed and ground on a Retsch mixer mill model MM200 for 20minutes at 30 Hertz.

Vapor Diffusion: A solution of (S)-TPMA besylate was prepared andfiltered into a vial. The vial was placed, uncapped, into a larger vialcontaining anti-solvent. The larger vial was capped, and the sample wasallowed to equilibrate.

Rotary Evaporation: A solution of (S)-TPMA besylate was prepared andfiltered. The sample was placed on a rotary evaporated at ambienttemperature and evaporated to dryness.

Lyophilization: An aqueous solution of (S)-TPMA besylate was prepared,filtered, and frozen using a dry ice/acetone bath. The sample was placedon an FTS-Systems Flexi-Dry lyophilizer.

Heating Experiments: A sample of (S)-TPMA besylate was placed in a vial,capped, and placed in an oil bath at a given temperature.

Instrumental Techniques

XRPD: Most XRPD patterns were collected with a PANalytical X'Pert PROMPD diffractometer using an incident beam of Cu radiation produced usingan Optix long, fine-focus source. An elliptically graded multilayermirror was used to focus Cu Kα X-rays through the specimen and onto thedetector. Prior to the analysis, a silicon specimen (NIST SRM 640d) wasanalyzed to verify the Si 111 peak position. A specimen of the samplewas sandwiched between 3 μm thick films and analyzed in transmissiongeometry. A beam-stop, short antiscatter extension, and antiscatterknife edge were used to minimize the background generated by air. Sollerslits for the incident and diffracted beams were used to minimizebroadening from axial divergence. Diffraction patterns were collectedusing a scanning position-sensitive detector (X'Celerator) located 240mm from the specimen and Data Collector software v. 2.2b. The dataacquisition parameters for each pattern are displayed above the image inthe Data section of this report including the divergence slit (DS)before the mirror and the incident-beam antiscatter slit (SS).

One XRPD pattern was collected with a PANalytical X'Pert PRO MPDdiffractometer using an incident beam of Cu Kα radiation produced usinga long, fine-focus source and a nickel filter. The diffractometer wasconfigured using the symmetric Bragg-Brentano. Prior to the analysis, asilicon specimen (NIST SRM 640d) was analyzed to verify the Si 111 peakposition. A specimen of the sample was prepared as a thin, circularlayer centered on a silicon zero-background substrate. Antiscatter slits(SS) were used to minimize the background generated by air. Soller slitsfor the incident and diffracted beams were used to minimize broadeningfrom axial divergence. The diffraction pattern was collected using ascanning position-sensitive detector (X'Celerator) located 240 mm fromthe sample and Data Collector software v. 2.2b. The data-acquisitionparameters for the pattern are displayed above the image in the Datasection of this report including the divergence slit (DS) and theincident-beam SS.

VT-XRPD (non-cGMP): VT-XRPD patterns were collected with a PANalyticalX'Pert PRO MPD diffractometer using an incident beam of Cu Kα radiationproduced using a long, fine-focus source and a nickel filter. Thediffractometer was configured using the symmetric Bragg-Brentanogeometry. Data were collected and analyzed using Data Collector softwarev. 2.2b. Prior to the analysis, a silicon specimen (NIST SRM 640d) wasanalyzed to verify the observed position of the Si 111 peak isconsistent with the NIST-certified position. A specimen of the samplewas packed in a nickel-coated copper well. Antiscatter slits (SS) wereused to minimize the background generated by air scattering. Sollerslits for the incident and diffracted beams were used to minimizebroadening from axial divergence. Diffraction patterns were collectedusing a scanning position-sensitive detector (X'Celerator) located 240mm from the sample. The data acquisition parameters for each pattern aredisplayed above the image in the Data section of this report includingthe divergence slit (DS) and the incident-beam SS.

An Anton Paar TTK 450 stage was used to collect in-situ XRPD patterns asa function of temperature. The sample was heated with a resistanceheater located directly under the sample holder, and the temperature wasmonitored with a platinum-100 resistance sensor located in the specimenholder. The heater was powered and controlled by an Anton Paar TCU 100interfaced with Data Collector.

Standard DSC: Standard DSC was performed using a TA Instruments Q2000differential scanning calorimeter. Temperature calibration was performedusing NIST traceable indium metal. The sample was placed into analuminum DSC pan, covered with a lid, the lid was crimped, and theweight was accurately recorded. (This pan configuration is designatedwith a “T0C” in the comments of the thermogram in the Data section.) Aweighed aluminum pan configured as the sample pan was placed on thereference side of the cell. The sample was heated from −30° C. to 250°C., at 10° C./min. (abbreviated as “−30-250-10” in the method field inthe thermogram).

Cycling Hyper-DSC: Hyper cycling-DSC was performed using a Perkin Elmerdiamond power compensated differential scanning calorimeter. Temperaturecalibration was performed using NIST traceable indium metal. The samplewas placed into an aluminum DSC pan, and the weight was accuratelyrecorded. The pan was covered with a lid, which was crimped. A weighed,crimped aluminum pan was placed on the reference side of the cell. Thesample cell was equilibrated at −50° C. and heated under a helium purgeat a rate of 100° C./min. to 145° C., where it was held for fiveminutes. The sample was then cooled at approximately 500° C./min. to−50° C. The sample was then heated to 50° C. at 100° C./min. and againcooled at approximately 500° C./min. to −50° C. Finally, the sample washeated at 100° C./min. to a final temperature of 150° C. It is notedthat the instrument was not calibrated for the 500° C./min. cooling, andthese cooling steps are considered to be “uncontrolled” cooling.

Hotstage Microscopy: Hot stage microscopy was performed using a Linkamhot stage (FTIR 600) mounted on a Leica DM LP microscope equipped with aSPOT Insight™ color digital camera. Temperature calibrations wereperformed using USP melting point standards. Samples were placed on acover glass, and a second cover glass was placed on top of the sample.As the stage was heated, each sample was visually observed using a20×0.40 N.A. long working distance objective with crossed polarizers anda first order red compensator. Images were captured using SPOT software(v. 4.5.9).

Optical Microscopy: Optical microscopy observations were made using aWolfe stereomicroscope with polarizers and a 2× or 4× objective.

Indexing (non-cGMP): The XRPD pattern of (S)-TPMA besylate Form BA wasindexed using proprietary SSCI software.

Indexing and structure refinement are computational studies which areperformed under the “Procedures for SSCI Non-cGMP Activities.”

Results

Approximate solubilities of (S)-TPMA besylate in different solvents showthat it has high solubility in methanol and water, as well as in aqueousmixtures.

TABLE 11a Approximate Solubilities of (S)-TPMA Besylate SolventApproximate Solubility^(a) Acetone 5 mg/mL 9:1 (v/v) Acetone: H₂O ≥92mg/mL ACN 26 mg/mL DCM 51 mg/mL EtOAc <2 mg/mL ^(b) EtOH 28 mg/mL IPA 8mg/mL 9:1 (v/v) IPA: H₂O ≥96 mg/mL MEK 1 mg/mL MeOH ≥116 mg/mL THF <1mg/mL ^(b) 9:1 (v/v) THF: H₂O ≥88 mg/mL Toluene <1 mg/mL ^(b) H₂O ≥108mg/mL ^(a): Solubility rounded to nearest mg/mL. Dissolution wasdetermined by visual inspection, and the actual solubility may be higherthan reported due to slow rates of dissolution or to addition ofover-sized aliquots. If dissolution was not observed, the solubility isreported as “less than”. If dissolution was observed upon addition ofthe first aliquot, the solubility is reported as “greater than or equalto”. ^(b) : Following the experiment at RT, the sample was set on a hotplate at ~68° C. Most solids dissolved at the solids dissolved at theelevated temperature. The elevated temperature observation is considerednon-cGMP, because the hot plate and thermometer identificationinformation were not documented.

Over 60 the (S)-TPMA beyslate polymorph crystallization experiments wereconducted during the screen. Types of experiments included evaporationand cooling at different rates, slurries, grinding with and withoutsolvent, anti-solvent crash precipitation, rotary evaporation, vapordiffusion, lyophilization, and a heating experiment. Isolated solidswere analyzed using XRPD. The XRPD patterns were compared to each otherand to the starting material.

Overall, material consistent with Form BA was obtained in the majorityof the experiments conducted. Selected samples of Form BA showed signsof preferred orientation, consistent with the observed plate-likemorphology. Material B was produced in a single experiment. Exhibitingsevere preferred orientation, Material B displayed an XRPD patternsimilar to that of Form BA with additional peaks. DSC and repeat XRPDdata collected on the material appeared to be consistent with Form BA,suggesting conversion. Attempts to reproduce Material B resulted in FormBA. X-ray amorphous (S)-TPMA was not produced during the polymorphexperiments.

Form BA

Hotstage microscopy data are presented in Table 11b. Based on thecombined characterization data, (S)-TPMA Form BA is a crystalline,stable, anhydrous, non-hygroscopic material with a melt at 142 to 143°C.

TABLE 11b Hotstage Microscopy Analysis Temperature Observation/Comments 24.9° C. Heating at 5° C./min  90.0° C. No apparent change 135.0° C. Noapparent change 140.8° C. Melting 142.0° C. Melting 142.2° C. Completemelt; start cooling. Melt was sharp. No noticeable discoloration of themelt was observed  62.1° C. Crystallization on cooling noted between~60-70° C.  50.0° C. Reheating 10° C./min to ~130° C., then 5° C./min.142.2° C. Final melt~melting point — Sample recrystallized on cooling

(S)-TPMA Form BA XRPD pattern was successfully indexed, suggesting thatthe sample is composed primarily of a single crystalline phase. See FIG.28 Agreement between the allowed peak positions, marked with red bars inthe figure, and the observed peaks indicates a consistent unit celldetermination. Space groups consistent with the assigned extinctionsymbol, unit cell parameters, and derived quantities are tabulated belowthe figure. To confirm the tentative indexing solution, the molecularpacking motifs within the crystallographic unit cells must bedetermined. No attempts at molecular packing were performed.

DSC data for (S)-TPMA Form BA revealed a single endothermic transitionat 142-143° C., attributable to a melt based on hotstage microscopyanalysis. The hotstage microscopy experiment did not show evidence ofdecomposition at the melt, and crystallization was observed uponcooling. Reheating of the sample revealed a melt at the same temperatureas the first melt, consistent with the sample crystallizing to the sameform. A VT-XRPD experiment indicated melt of Form BA crystallized toForm A upon cooling. Specifically, at room temperature, Form BA isobserved, at 145° C. (ramp rate from room temperature is 35° C./min)shows a halo indicative of melt, and −60 to −90° C. shows Form BA withsome disorder.

Material B

Material B was obtained once from an acetone slow cool experiment from45° C. The XRPD pattern for the material exhibited severe preferredorientation effects and showed few peaks. While some of the peaksappeared to be consistent with Form BA, additional peaks were observedthat are likely not associated with Form BA. The observed additionalpeaks do not appear to arise from either (S)-TPMA free base or frombenzenesulfonic acid.

The Material B sample was analyzed using DSC. The resulting thermogramwas not distinguishable from that of Form BA. Subsequent, repeat XRPDanalysis of the sample revealed conversion to Form BA. Additionalexperiments were attempted targeting Material B. Selected samples wereanalyzed wet under the assumption the material may be an unstablesolvate. The experiments, however, resulted in Form BA, based on XRPDdata. Alternatively, Material B may represent a mixture of primarilyForm A with a low-level contaminant.

Amorphous Material

Amorphous (S)-TPMA besyalte has a glass transition temperature atapproximately 20° C., and tends to crystallize to Form A.

In summary, a polymorph study of (S)-TPMA was conducted to estimate thenumber and types of solid forms. Overall, one crystalline form,designated as Form BA, was observed during the majority of the screenexperiments. Characterization data indicated (S)-TPMA besylate Form A isa crystalline, stable, anhydrous, non-hygroscopic material with a meltin the range of 142 to 143° C. One experiment resulted in Material B,suggesting the existence of another possible form. Attempts to reproducethe material resulted in Form BA. Finally, amorphous (S)-TPMA besylateappears to be unstable, exhibits a glass transition temperature atapproximately 20° C., and tends to crystallize to Form A.

Example 12. Crystalline Form of (S)-TPMA Free Base

The crystalline form of (S)-TPMA free base was analyzed using XRPD, DSC,coulometric titration, and DVS. FIG. 32 shows the XRPD and Table 12aprovides a list of the peaks of Form BA.

TABLE 12a (S)-TPMA free base XRPD (FIG. 32) Peak List 2-Theta (degree)Relative height (%)  6.8 0.9  9.3 1.0 11.2 1.9 12.1 6.0 13.6 8.8 14.85.3 15.1 0.5 15.4 1.1 16.4 14.7 17.5 3.4 18.0 1.5 20.0 20.9 20.4 100.021.3 0.9 21.9 1.5 22.4 11.6 23.2 13.9 24.0 1.2 24.4 2.7 25.3 1.2 26.28.6 26.6 9.7 27.3 54.0 27.7 8.5 27.9 5.1 29.0 1.9 29.3 0.9 31.2 2.6 31.81.1 32.1 0.7 32.7 1.0 34.1 1.0 34.4 1.9 35.0 0.7 35.6 5.4 36.3 0.6 38.80.6 39.7 3.9 40.7 2.1 42.0 2.2 42.6 0.8 43.5 1.3 43.9 1.8 44.6 0.7

Example 13. PSD and Agglomeration Control in Scale-Up ofReactive-Crystallization

The agglomeration and Particle Size Distribution (PSD) of(S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine HClForm A Crystals have been investigated and successfully implementedduring scale-up to industrial scale manufacturing.

The results indicated that the mixing control and flow dynamics areaffect agglomeration and PSD control. The mesomixing time, when theincoming HCl solution stream mixes with the bulk freebase solution,plays a role in terms of the agglomeration and PSD control. Therefore,it is necessary to understand the flow pattern and the mixing behaviorof the reactors with Computational Fluid Dynamics (CFD) calculationthrough simulation tools.

In order to address the agglomeration and PSD, certain processparameters were identified, including the dosing types (subsurfaceaddition, or overhead addition), dosing tubing discharge location insubsurface addition (well defined mixing zone, or dead zone), diameterof the dosing tubing (which affects the meso-mixing time), dosingprofiles of the HCl stream (dosing rate).

A series of studies were conducted on various aspects of thereactive-recrystallization (e.g. Scheme 4 in Example 1A) to developmethods and provide various particle size distribution of (S)-(−)-TPMAHCl Form A crystals. Reaction conditions were substantially similar tothose set for in Example 1A with respect to Scheme 4 except as modifiedas described in the studies below.

Study 1.

Elimination of agglomeration in the final crystallization of(S)-(−)-TPMA HCl was demonstrated through use of controlled sub-surfaceaddition of the acid stream at the region of a high mixing zone near theimpeller tip. FIG. 29 illustrates the impact of such controlled additionof two different addition points: when adding the acid stream into thecenter of the free base solution the resulting morphology is that of anagglomerate form. When adding the acid stream below surface and near theimpeller tip (FIG. 29), the resulting morphology is that of anagglomerate free and larger size crystalline product.

Study 2.

For any crystallization process, the balance between nucleation, crystalgrowth and agglomeration determine the size distribution, and thesupersaturation generation rate could be the driving force for thecrystallization and the decisive parameter to balance the nucleation andcrystal growth, etc.

In the current reactive-crystallization of (S)-TPMA HCl, thesupersaturation generation rate can be directly controlled by the HClsolution addition rate. A series of experiments have been executed withdifferent HCl addition profiles effect on particle size distribution.The results summarized in Table 13A and Table 13B and FIG. 30 and FIG.31 indicate that faster dosing favorites the formation of the smallercrystals and slower dosing favorites the formation of bigger crystals.

TABLE 13A HCl IPA Solution Dosing Profiles Profile HCl IPA solutionaddition 10 min × 3, (i) first 10% added over approximately 10 minutesHCl dosing (ii) next 30% added over approximately 10 minutes (iii)remainder added over approximately 10 minutes 15 min × 3, (i) first 10%added over approximately 15 minutes HCl dosing (ii) next 30% added overapproximately 15 minutes (iii) remainder added over approximately 15minutes 20 min × 3, (i) first 10% added over approximately 20 minutesHCl dosing (ii) next 30% added over approximately 20 minutes (iii)remainder added over approximately 20 minutes 30 min × 3, (i) first 10%added over approximately 30 minutes HCl dosing (ii) next 30% added overapproximately 30 minutes (iii) remainder added over approximately 30minutes

TABLE 13B Particle Size Distribution Parameters for Dosing ProfilesSample Name D (4,3) d (0.1) d (0.5) d (0.9) Span 10 min × 3, HCl 149.4355.23 131.21 273.25 1.662 Dosing 15 min × 3, HCl 185.80 79.73 167.51323.92 1.458 dosing 20 min × 3, HCl 209.45 103.82 199.11 335.44 1.163dosing 30 min × 3, HCl 222.06 129.01 209.38 334.41 0.981 dosing Note: 1mm ID dosing tubing, operating temperature: 20° C.Study 3.

The PSD control strategy has been implemented and demonstratedeffectively during the process scale-up to manufacturing plant (100 Kginput). Using a sub-surface addition and maintaining a mesomixing timeconstant during scale-up a simple acid addition profile change fromProfile A to profile B results to a mean size decrease from ˜175 μm to asize of ˜100 μm (D50).

Dosing Profiles D10 D50 D90 D(4, 3) Span Quantity, Kg Dosing Profile A67.6 176.2 359.8 196.9 1.66 61.32 Dosing Profile B 46.1 108.0 239.4128.0 1.79 69.90 dosing Profile A: The first 10%: add over approximately90 minutes; the next 30%: add over approximately 45 minutes; theremainder: add over approximately 45 minutes; Dosing Profile B: Thefirst 10%: add over approximately 15 minutes; the next 30%: add overapproximately 15 minutes; the remainder: add over approximately 18minutes.

The Diagnostic and Statistical Manual of Mental Disorders, Fifth Ed.,hereinafter, the “DSM-5”), published by the American PsychiatricAssociation in 2013, and is incorporated herein by reference, provides astandard diagnostic system upon which persons of skill rely fordiagnosis of various diseases and disorders.

The term “mood disorder” as used herein includes depression, majordepression, major depressive disorder, mild depression, severedepression without psychosis, severe depression with psychosis,melancholia (formerly endogenous depression), atypical depression,dysthymic disorder, manic depression, bipolar disorder, bipolardepression, bipolar I disorder, bipolar II disorder, bipolar IIIdisorder, cyclothymic disorder, and chronic hypomania.

Psychiatric disorders are pathological conditions of the braincharacterized by identifiable symptoms that result in abnormalities incognition, emotion or mood, or the highest integrative aspects ofbehavior. These disorders may vary in severity of symptoms, duration,and functional impairment. Psychiatric disorders afflict millions ofpeople worldwide resulting in tremendous human suffering and economicburden due to lost productivity. Mood disorders are a type ofpsychiatric disorder often defined as a group of heterogeneous,typically recurrent illnesses including unipolar (depressive) andbipolar (manic-depressive) disorders characterized by pervasive mooddisturbances, psychomotor dysfunction, and vegetative symptoms. Suicide,the most serious complication in patients with mood disorders, is thecause of death in 15 to 25% of untreated patients with mood disorders;unrecognized or inadequately treated depression contributes to 50 to 70%of all completed suicides.

In various embodiments, the neurological disorder is: depression (e.g.,major depressive disorder or dysthymia); bipolar disorder, seasonalaffective disorder; cognitive deficit; fibromyalgia; pain (e.g.,neuropathic pain); sleep related disorder (e.g., sleep apnea, insomnia,narcolepsy, cataplexy) including those sleep disorders which areproduced by psychiatric conditions; chronic fatigue syndrome; attentiondeficit disorder (ADD); attention deficit hyperactivity disorder (ADHD);restless leg syndrome; schizophrenia; anxieties (e.g., general anxietydisorder, social anxiety disorder, panic disorder); obsessive compulsivedisorder; post-traumatic stress disorder; seasonal affective disorder(SAD); premenstrual dysphoria; post-menopausal vasomotor symptoms (e.g.,hot flashes, night sweats); neurodegenerative disease (e.g., Parkinson'sdisease, Alzheimer's disease and amyotrophic lateral sclerosis); manicdisorder; dysthymic disorder; cyclothymic disorder; obesity; andsubstance abuse or dependency (e.g., cocaine addiction, nicotineaddiction). In another embodiment, the compounds provided herein areuseful to treat, prevent, and/or manage two or moreconditions/disorders, which are co-morbid, such as psychosis anddepression.

Neurological disorders may also include cerebral function disorders,including without limitation, senile dementia, Alzheimer's typedementia, cognition, memory loss, amnesia/amnestic syndrome, epilepsy,disturbances of consciousness, coma, lowering of attention, speechdisorder, Lennox syndrome, autism, and hyperkinetic syndrome.

In various aspects, the disease or disorder which the medicaments andmethods of the present inventions treat comprises one of more of a mooddisorder, bipolar disorder (BPD), bipolar depression, sleep disorders,REM behavior disorder, psychosis disorders, Alzheimer's disease withagitation and/or psychosis, Parkinson's disease psychosis,schizophrenia, attenuated psychosis syndrome, prodromal schizophrenia,and schizoaffective disorder.

In various embodiments, the neurological or psychiatric disease ordisorder is one or more of a mood disorder, bipolar disorder (BPD),bipolar depression, sleep disorders, REM behavior disorder, psychosisdisorders, Alzheimer's disease with agitation and/or psychosis,Parkinson's disease psychosis, schizophrenia, attenuated psychosissyndrome, prodromal schizophrenia, and schizoaffective disorder.

In various embodiments, the neurological or psychiatric disease ordisorder is selected from a psychosis, including schizophrenia(paranoid, disorganized, catatonic or undifferentiated),schizophreniform disorder, schizoaffective disorder, delusionaldisorder, brief psychotic disorder, shared psychotic disorder,psychoaffective disorder, aggression, delirium, Parkinson's psychosis,excitative psychosis, psychotic disorder due to a general medicalcondition and substance-induced or drug-induced (e.g., phencyclidine,ketamine and other dissociative anesthetics, amphetamine and otherpsychostimulants and cocaine) psychosis disorder, psychosis associatedwith affective disorders, brief reactive psychosis, schizoaffectivepsychosis, “schizophrenia-spectrum” disorders such as schizoid orschizotypal personality disorders, or illness associated with psychosis(such as major depression, manic depressive (bipolar) disorder,Alzheimer's disease and post-traumatic stress syndrome), including bothpositive, negative, and cognitive symptoms of schizophrenia and otherpsychoses; anxiety disorders including acute stress disorder,agoraphobia, generalized anxiety disorder, obsessive-compulsivedisorder, panic attack, panic disorder, post-traumatic stress disorder,separation anxiety disorder, social phobia, specific phobia,substance-induced anxiety disorder and anxiety due to a general medicalcondition; substance-related disorders and addictive behaviors(including substance-induced delirium, persisting dementia, persistingamnestic disorder, psychotic disorder or anxiety disorder; tolerance,dependence or withdrawal from substances including alcohol,amphetamines, cannabis, cocaine, hallucinogens, inhalants, nicotine,opioids, phencyclidine, sedatives, hypnotics or anxiolytics); andAlzheimer's disease with agitation and/or psychosis.

In some embodiments, provided herein is a method of treatingschizophrenia comprising administering to the subject a formulation(e.g., tablet) as described herein, in the amount of about 25 mg toabout 100 mg per day of (S)-TPMA, or pharmaceutically acceptable saltthereof, on a free base basis. In some embodiments, the amount is about25 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg,about 75 mg, about 80 mg, about 90 mg, or about 100 mg per day of(S)-TPMA, or pharmaceutically acceptable salt thereof, on a free basebasis.

In various embodiments, the neurological or psychiatric disease ordisorder is selected from a depressive disorders including, but notlimited to, unipolar depression, seasonal depression and post-partumdepression, atypical depression, catatonic depression, elderlydepression, endogenous depression, melancholic depression, perinataldepression, situational depression, chronic depression, bipolardepression, major depressive disorder (MDD), major depressive disorderwith mixed features (MDD-MF), treatment resistant depression (TRD), anddysthymia, and are associated with depressed mood (sadness), poorconcentration, insomnia, fatigue, appetite disturbances, excessive guiltand thoughts of suicide, premenstrual syndrome (PMS) and premenstrualdysphoric disorder (PDD), mood disorders due to a general medicalcondition, and substance-induced mood disorders.

In various embodiments, the neurological or psychiatric disease ordisorder is selected from a bipolar disorders including, but not limitedto, bipolar depression, bipolar I disorder, bipolar II disorder,cyclothymic disorder, substance/medication-induced bipolar and relateddisorders, bipolar and related disorder due to another medicalcondition, other specified bipolar and related disorder, and unspecifiedbipolar and related disorders.

In various embodiments, the neurological or psychiatric disease ordisorder is selected from an eating disorder including, but not limitedto, eating disorders such as obesity, bulimia nervosa, pica andcompulsive eating disorders.

In various embodiments, the neurological or psychiatric disease ordisorder is selected from a sleep disorder including, but not limitedto, insomnia, disturbed sleep, jet lag, hypersomnia, cataplexy, sleepapnea, obstructive sleep apnea, REM sleep behavior disorder, RestlessLeg Syndrome, periodic limb movement disorder, circadian rhythm sleepdisorders, delayed sleep phase disorder, sleepwalking, night terrors,bed wetting, rapid eye movement sleep behavior disorder, shift worksleep disorder, excessive daytime sleepiness, non-24-hour sleep-wakedisorder, sleep paralysis and narcolepsy.

In various embodiments, the neurological or psychiatric disease ordisorder is a bipolar disorder. Bipolar disorders (including bothbipolar I and bipolar II) are serious psychiatric disorders that have aprevalence of approximately 2% of the population, and affect bothgenders alike. It is a relapsing-remitting condition characterized bycycling between elevated (i.e., manic) and depressed moods, whichdistinguishes it from other disorders such as major depressive disorderand schizophrenia. Bipolar I is defined by the occurrence of a fullmanic episode, although most individuals experience significantdepression. Symptoms of mania include elevated or irritable mood,hyperactivity, grandiosity, decreased need for sleep, racing thoughtsand in some cases, psychosis. The depressive episodes are characterizedby anhedonia, sad mood, hopelessness, poor self-esteem, diminishedconcentration and lethargy. Bipolar II is defined as the occurrence of amajor depressive episode and hypomanic (less severe mania) episodealthough patients spend considerable more time in the depressive state.Other related conditions include cyclothymic disorder.

In bipolar I disorder, full-fledged manic and major depressive episodesalternate. Bipolar I disorder commonly begins with depression and ischaracterized by at least one manic or excited period during its course.The depressive phase can be an immediate prelude or aftermath of mania,or depression and mania can be separated by months or years.

In bipolar II disorder, depressive episodes alternate with hypomanias(relatively mild, nonpsychotic periods of usually <1 week). During thehypomanic period, mood brightens, the need for sleep decreases, andpsychomotor activity accelerates beyond the patient's usual level.Often, the switch is induced by circadian factors (e.g., going to beddepressed and waking early in the morning in a hypomanic state).Hypersomnia and overeating are characteristic and may recur seasonally(e.g., in autumn or winter); insomnia and poor appetite occur during thedepressive phase. For some persons, hypomanic periods are adaptivebecause they are associated with high energy, confidence, andsupernormal social functioning. Many patients who experience pleasantelevation of mood, usually at the end of a depression, do not report itunless specifically questioned.

Patients with major depressive episodes and a family history of bipolardisorders (unofficially called bipolar III) often exhibit subtlehypomanic tendencies; their temperament is termed hyperthymic (i.e.,driven, ambitious, and achievement-oriented).

In cyclothymic disorder, less severe hypomanic and mini-depressiveperiods follow an irregular course, with each period lasting a few days.Cyclothymic disorder is commonly a precursor of bipolar II disorder. Butit can also occur as extreme moodiness without being complicated bymajor mood disorders. In such cases, brief cycles of retarded depressionaccompanied by low self-confidence and increased sleep alternate withelation or increased enthusiasm and shortened sleep. In another form,low-grade depressive features predominate; the bipolar tendency is shownprimarily by how easily elation or irritability is induced byantidepressants. In chronic hypomania, a form rarely seen clinically,elated periods predominate, with habitual reduction of sleep to <6hours. Persons with this form are constantly overcheerful, self-assured,overenergetic, full of plans, improvident, overinvolved, and meddlesome;they rush off with restless impulses and accost people.

Accordingly, in various embodiments, the neurological or psychiatricdisease or disorder is one or more of bipolar I disorder, bipolar IIdisorder, cyclothymic disorder, other specified bipolar and relateddisorder, or unspecified bipolar and related disorder, and bipolar Idisorder or bipolar II disorder with the specifiers of anxious distress,with mixed features, with rapid cycling, with melancholic features, withatypical features, with mood-congruent psychotic features, with moodincongruent psychotic features, with catatonia, with peripartum onset,and/or with seasonal pattern. A recent article by Hu et al [Prim CareCompanion CNS Disord. 2014; 16(2): PCC.13r01599] highlights that bipolardisorder, while commonly encountered in the primary care setting, isoften misdiagnosed or undiagnosed. The DSM-5 attempts to capture thelarge proportion of patients with subsyndromal mixed symptoms with theinclusion of the mixed specifier.

In various embodiments, the neurological or psychiatric disease ordisorder is a depressive disorder. Depressive disorders include, but arenot limited to, depressive disorders including, but not limited to,unipolar depression, seasonal depression and post-partum depression,atypical depression, catatonic depression, elderly depression,endogenous depression, melancholic depression, perinatal depression,situational depression, chronic depression, bipolar depression, majordepressive disorder (MDD), major depressive disorder with mixed features(MDD-MF), treatment resistant depression (TRD), and dysthymia, and areassociated with depressed mood (sadness), poor concentration, insomnia,fatigue, appetite disturbances, excessive guilt and thoughts of suicide,premenstrual syndrome (PMS) and premenstrual dysphoric disorder (PDD),mood disorders due to a general medical condition, and substance-inducedmood disorders.

Depression is an affective disorder, the pathogenesis of which cannot beexplained by any single cause or theory. Unfortunately, treatmentoptions for depressed patients who have suboptimal clinical responses totherapy with an antidepressant are limited. Approximately thirty percent(30%) of patients initiating antidepressant therapy show suboptimal ordelayed clinical responses to the first-line antidepressant agents thatare commonly used to treat depression.

Typically, if a patient exhibits suboptimal or delayed clinical responseafter several weeks of therapy with an antidepressant, the clinician'sinitial approach is to increase the dose of the antidepressant. If thepatient's response remains unsatisfactory after increasing the dose, themost common approaches that many clinicians will pursue are: a)switching to another antidepressant; or b) adding a secondantidepressant; or c) attempting an augmentation therapy byadministering agents such as lithium carbonate, thyroid hormone(triiodothyronine), psychostimulants, modafinil, atypicalantipsychotics, buspirone, or pindolol.

In its full syndromal expression, clinical depression manifests as majordepressive disorder, with episodic course and varying degrees ofresidual manifestations between episodes. The mood is typicallydepressed, irritable, and/or anxious. The patient may appear miserable,with furrowed brows, downturned corners of the mouth, slumped posture,poor eye contact, and monosyllabic (or absent) speech. The morbid moodmay be accompanied by preoccupation with guilt, self-denigrating ideas,decreased ability to concentrate, indecisiveness, diminished interest inusual activities, social withdrawal, helplessness, hopelessness, andrecurrent thoughts of death and suicide. Sleep disorders are common. Insome, the morbid mood is so deep that tears dry up; the patientcomplains of an inability to experience usual emotions—including grief,joy, and pleasure—and of a feeling that the world has become colorless,lifeless, and dead.

Melancholia (formerly endogenous depression) is characterized by markedpsychomotor slowing (of thinking and activity) or agitation (e.g.,restlessness, wringing of the hands, pressure of speech), weight loss,irrational guilt, and loss of the capacity to experience pleasure. Moodand activity vary diurnally, with a nadir in the morning. Mostmelancholic patients complain of difficulty falling asleep, multiplearousals, and insomnia in the middle of the night or early morning.Sexual desire is often diminished or lost. Amenorrhea can occur.Anorexia and weight loss may lead to emaciation and secondarydisturbances in electrolyte balance.

In atypical depression, reverse vegetative features dominate theclinical presentation; they include anxious-phobic symptoms, eveningworsening, initial insomnia, hypersomnia that often extends into theday, and hyperphagia with weight gain. Unlike patients with melancholia,those with atypical depression show mood brightening to potentiallypositive events but often crash into a paralyzing depression with theslightest adversity. Atypical depressive and bipolar II disordersoverlap considerably.

In dysthymic disorder, depressive symptoms typically begin insidiouslyin childhood or adolescence and pursue an intermittent or low-gradecourse over many years or decades; major depressive episodes maycomplicate it (double depression). In pure dysthymia, depressivemanifestations occur at a subthreshold level and overlap considerablywith those of a depressive temperament: habitually gloomy, pessimistic,humorless, or incapable of fun; passive and lethargic; introverted;skeptical, hypercritical, or complaining; self-critical,self-reproaching, and self-derogatory; and preoccupied with inadequacy,failure, and negative events.

Thorough evaluation of many persons with depression reveals bipolartraits, and as many as one in five patients with a depressive disorderalso develops frank hypomania or mania. Most switches from unipolar tobipolar disorder occur within 5 years of the onset of depressivemanifestations. Predictors of a switch include early onset of depression(<25 years old), postpartum depression, frequent episodes of depression,quick brightening of mood with somatic treatments (e.g.,antidepressants, phototherapy, sleep deprivation, electroconvulsivetherapy), and a family history of mood disorders for three consecutivegenerations.

Between episodes, patients with bipolar disorder exhibit depressivemoodiness and sometimes high-energy activity; disruption indevelopmental and social functioning in bipolar depression is morecommon than in unipolar disorder. In bipolar disorder, depressionepisodes are shorter (3 to 6 months), age of onset is younger, onset ofepisodes is more abrupt, and cycles (time from onset of one episode tothat of the next) are shorter than in unipolar disorder. Cyclicity isparticularly accentuated in rapid-cycling forms of bipolar disorder(usually defined as >=4 episodes/year). In addition depressive episodesin bipolar disorder are a difficult component of BPD to treat. Forexample, psychiatrists indicate that about 25% of patients across allbipolar disorders are refractory during a manic episode, while about 70%are refractory during a depressive episode.

Accordingly, in various embodiments, the neurological or psychiatricdisease or disorder is one or more of bipolar depression, majordepressive disorder (MDD), persistent depressive disorder (Dysthymia),premenstrual dysphoric disorder (PMDD), major depressive disorder withmixed features (MDD-MF), depressive disorder due to another medicalcondition, other specified depressive disorder, unspecified depressivedisorder, or treatment resistant depression (TRD), and MDD with thespecifiers of anxious distress, with mixed features, with melancholicfeatures, with atypical features, with mood-congruent psychoticfeatures, with mood-incongruent psychotic features, with catatonia, withperipartum onset, and/or with seasonal pattern, and seasonal affectivedisorder.

It is to be understood that TRD is a term used in clinical psychiatry todescribe cases of major depressive disorder (MDD) that do not respondadequately to appropriate courses of at least two antidepressants.

In various embodiments, a depressive disorder is associated with acutesuicidality or suicide ideation. The United States Food and DrugAdministration has adopted a “black box” label warning indicating thatantidepressants may increase the risk of suicidal thinking and behaviorin some children, adolescents and young adults (up to age 24) with adepressive disorder such as MDD. In various embodiments, it is believedthat the compositions and methods of the present inventions do notincrease the risk of suicidal thinking and/or behavior in children,adolescents and/or young adults with a depressive disorder, e.g., withMDD. In various embodiments, the present inventions provide medicamentsfor and provide methods of treating one or more symptoms of a depressivedisorder (e.g., MDD) in children, adolescents and/or young adultswithout increasing the risk of suicidal thinking and/or behavior.

In various embodiments, the neurological or psychiatric disease ordisorder is schizophrenia. Schizophrenia is a disorder of unknownorigin, which usually appears for the first time in early adulthood andis marked by characteristics such as psychotic symptoms, phasicprogression and development, and/or deterioration in social behavior andprofessional capability. Characteristic psychotic symptoms are disordersof thought content (e.g., multiple, fragmentary, incoherent, implausibleor simply delusional contents, or ideas of persecution) and of mentality(e.g., loss of association, flight of imagination, incoherence up toincomprehensibility), as well as disorders of perceptibility (e.g.,hallucinations), emotions (e.g., superficial or inadequate emotions),self-perceptions, intentions, impulses, and/or inter-humanrelationships, and psychomotoric disorders (e.g., catatonia). Othersymptoms are also associated with this disorder. Schizophrenia isclassified into subgroups: the paranoid type, characterized by delusionsand hallucinations and absence of thought disorder, disorganizedbehavior, and affective flattening; the disorganized type, also named“hebephrenic schizophrenia,” in which thought disorder and flat affectare present together; the catatonic type, in which prominent psychomotordisturbances are evident, and symptoms may include catatonic stupor andwaxy flexibility; and the undifferentiated type, in which psychoticsymptoms are present but the criteria for paranoid, disorganized, orcatatonic types have not been met. The symptoms of schizophrenianormally manifest themselves in three broad categories: positive,negative and cognitive symptoms. Positive symptoms are those whichrepresent an “excess” of normal experiences, such as hallucinations anddelusions. Negative symptoms are those where the patient suffers from alack of normal experiences, such as anhedonia and lack of socialinteraction. The cognitive symptoms relate to cognitive impairment inschizophrenics, such as lack of sustained attention and deficits indecision making.

Accordingly, in various embodiments, the neurological or psychiatricdisease or disorder is one or more of schizotypal (personality)disorder, delusional disorder, brief psychotic disorder,schizophreniform disorder, schizophrenia, schizoaffective disorder,substance/medication-induced psychotic disorder, psychotic disorder dueto another medical condition, other specified schizophrenia spectrum andother psychotic disorder, unspecified schizophrenia spectrum, and otherpsychotic disorder.

It is to be understood that schizoaffective disorder includes acondition that includes aspects of both schizophrenia and a mooddisorder, such as, for example, a major depressive disorder, a bipolardisorder, etc.

In various embodiments, the neurological or psychiatric disease ordisorder is anxiety disorder. Anxiety disorders are characterized byfear, worry, and uneasiness, usually generalized and unfocused as anoverreaction to a situation. Anxiety disorders differ in the situationsor types of objects that induce fear, anxiety, or avoidance behavior,and the associated cognitive ideation. Anxiety differs from fear in thatanxiety is an emotional response to a perceived future threat while fearis associated with a perceived or real immediate threat. They alsodiffer in the content of the associated thoughts or beliefs. Examples ofanxiety disorders include separation anxiety disorder, selective mutism,specific phobia, social anxiety disorder (social phobia), panicdisorder, panic attack specifier, agoraphobia, generalized anxietydisorder, substance/medication-induced anxiety disorder, anxietydisorder due to another medical condition, illness anxiety disorder,social (pragmatic) communication disorder, other specified anxietydisorder, and unspecified anxiety disorder; stressor-related disorders,including reactive attachment disorder, disinhibited social engagementdisorder, posttraumatic stress disorder (PTSD), acute stress disorder,and adjustment disorders.

In various embodiments, the neurological or psychiatric disease ordisorder is a sleep disorder including those sleep disorders which areproduced by psychiatric conditions, including, but not limited to,insomnia, disturbed sleep, jet lag, hypersomnia, cataplexy, sleeprelated disorder (e.g., sleep apnea, insomnia, narcolepsy, cataplexy),obstructive sleep apnea, REM sleep behavior disorder, Restless LegSyndrome, periodic limb movement disorder, circadian rhythm sleepdisorders, delayed sleep phase disorder, sleepwalking, night terrors,bed wetting, rapid eye movement sleep behavior disorder, shift worksleep disorder, excessive daytime sleepiness, non-24-hour sleep-wakedisorder, sleep paralysis and narcolepsy.

Provided herein are also the following embodiments.

Embodiment 1. A formulation comprising a salt of(S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine and oneor more excipients, wherein the amount of the salt of(S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine isabout 2 to about 80% w/w, on a free base basis.Embodiment 2. The formulation of embodiment 1, wherein the salt of(S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine isselected from:

-   (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine    hydrochloride,-   (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine    besylate,-   (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine    R-mandelate,-   (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine    L-tartrate,-   (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine    D-tartrate,-   (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine    mesylate, and-   (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine    L-malate.    Embodiment 3. The formulation of embodiment 2, wherein the salt of    (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine is    crystalline.    Embodiment 4. The formulation of embodiment 3, wherein the    crystalline    (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine    hydrochloride is characterized by a powder x-ray diffraction pattern    comprising peaks, in terms of 2-theta, at 9.6±0.2°, 14.9±0.2°,    20.5±0.2, and 25.1±0.2°.    Embodiment 5. The formulation of embodiment 4, wherein the    crystalline    (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine    hydrochloride is further characterized by the powder x-ray    diffraction pattern further comprising a peak, in terms of 2-theta,    at 20.2±0.2° and 20.8±0.2°.    Embodiment 6. The formulation of embodiment 4 or embodiment 5,    wherein the crystalline    (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine    hydrochloride is further characterized by the powder x-ray    diffraction pattern further comprising a prominent peak, in terms of    2-theta, at two or more of 17.9±0.2°, 24.8±0.2° and 27.1±0.2°.    Embodiment 7. The formulation of any one of embodiments 4-6, wherein    the crystalline    (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine    hydrochloride is characterized by a powder x-ray diffraction pattern    substantially in accord with FIG. 2B.    Embodiment 8. The formulation of any one of embodiments 4-7, wherein    the crystalline    (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine    hydrochloride has a differential scanning calorimetry thermogram    comprising a peak at 214±2° C.    Embodiment 9. The formulation of any one of embodiments 4-8, wherein    the crystalline    (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine    hydrochloride has a differential scanning calorimetry thermogram    substantially in accord with FIG. 3A.    Embodiment 10. The formulation of any one of embodiments 3-9,    wherein the crystalline    (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine    hydrochloride is characterized by monoclinic space group P21.    Embodiment 11. The formulation of any one of embodiments 3-10,    wherein the crystalline    (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine    hydrochloride has unit cell dimensions: a is about 9.2 Å, b is about    11.2 Å, c is about 10.2 Å, α is about 90°, β is about 92°, and γ is    about 90°.    Embodiment 12. The formulation of any one of embodiments 3-11,    wherein the crystalline    (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine    hydrochloride has chiral purity greater than about 90%    (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine    hydrochloride.    Embodiment 13. The formulation of any one of embodiments 3-12,    wherein the crystalline    (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine    hydrochloride has chemical purity of the substance is greater than    about 99%    (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine    hydrochloride.    Embodiment 14. The formulation of embodiment 3, wherein the    crystalline    (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine    hydrochloride is characterized by a powder x-ray diffraction pattern    comprising peaks, in terms of 2-theta, at 8.6±0.2°, 17.2±0.2°, and    25.9±0.2°.    Embodiment 15. The formulation of embodiment 14, wherein the    crystalline    (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine    hydrochloride is characterized by a powder x-ray diffraction pattern    substantially in accord with FIG. 2C.    Embodiment 16. The formulation of embodiment 14 or embodiment 15,    wherein the crystalline    (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine    hydrochloride has a differential scanning calorimetry thermogram    comprising a peak at 215±2° C.    Embodiment 17. The formulation of any one of embodiments 14-16,    wherein the crystalline    (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine    hydrochloride has a differential scanning calorimetry thermogram    substantially in accord with FIG. 3B.    Embodiment 18. The formulation of any one of embodiments 14-17,    wherein the crystalline    (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine    hydrochloride is characterized by orthorhombic space group P212121.    Embodiment 19. The formulation of any one of embodiments 3, and    14-17, wherein the crystalline    (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine    hydrochloride has unit cell dimensions: a is about 5.1 Å, b is about    10.2 Å, c is about 20.5 Å, α is about 90°, β is about 90°, and γ is    about 90°.    Embodiment 20. The formulation of embodiment 2, wherein the salt of    (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine is    (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine    besylate.    Embodiment 21. The formulation of embodiment 2, wherein the salt of    (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine is    (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine    R-mandelate.    Embodiment 22. The formulation of embodiment 2, wherein the salt of    (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine is    (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine    L-tartrate.    Embodiment 23. The formulation of embodiment 2, wherein the salt of    (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine is    (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine    D-tartrate.    Embodiment 24. The formulation of embodiment 2, wherein the salt of    (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine is    (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine    mesylate.    Embodiment 25. The formulation of embodiment 2, wherein the salt of    (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine is    (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine    L-malate.    Embodiment 26. The formulation of any one of embodiments 1-25,    wherein the formulation is a tablet.    Embodiment 27. The formulation of any one of embodiments 1-26,    wherein the amount of the salt of    (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine is    about 50 to about 80% w/w.    Embodiment 28. The formulation of any one of embodiments 1-26,    wherein the amount of the salt of    (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine is    about 60 to about 80% w/w.    Embodiment 29. The formulation of any one of embodiments 1-26,    wherein the amount of the salt of    (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine is    about 70% w/w.    Embodiment 30. The formulation of any one of embodiments 1-29,    wherein the excipient is one or more fillers.    Embodiment 31. The formulation of embodiment 30, wherein the amount    of the filler is about 10 to about 50% w/w.    Embodiment 32. The formulation of embodiment 30, wherein the amount    of the filler is about 20 to about 40% w/w.    Embodiment 33. The formulation of any one of embodiments 30-33,    wherein the filler is microcrystalline cellulose, mannitol, or a    mixture thereof.    Embodiment 34. The formulation of any one of embodiments 1-33,    wherein the excipient is one or more disintegrants.    Embodiment 35. The formulation of embodiment 34, wherein the amount    of the disintegrant is about 0.5 to about 10% w/w.    Embodiment 36. The formulation of embodiment 35, wherein the amount    of the disintegrant is about 1 to about 5% w/w.    Embodiment 37. The formulation of embodiment 35, wherein the amount    of the disintegrant is about 2% w/w.    Embodiment 38. The formulation of embodiment 37, wherein the    disintegrant is sodium starch glycolate.    Embodiment 39. The formulation of any one of embodiments 1-38,    wherein the excipient comprises one or more lubricants.    Embodiment 40. The formulation of embodiment 39, wherein the amount    of the lubricant is about 0.1 to about 0.5% w/w.    Embodiment 41. The formulation of embodiment 39, wherein the amount    of the lubricant is about 0.2% w/w.    Embodiment 42. The formulation of embodiment 41, wherein the    lubricant is magnesium stearate.    Embodiment 43. The formulation of any one of embodiments 1-42    further comprises a coating.    Embodiment 44. The formulation of any one of embodiments 1-29    comprising a salt of    (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine,    filler, disintegrant, and lubricant.    Embodiment 45. The formulation of any one of embodiments 1-19    comprising    (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine    hydrochloride, filler, disintegrant, and lubricant.    Embodiment 46. The formulation of any one of embodiments 1-19 and 45    comprising    (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine    hydrochloride, microcrystalline cellulose, mannitol, sodium starch    glycolate, and magnesium stearate.    Embodiment 47. A method of treating a neurological disease or    disorder, comprising administering to a subject a therapeutically    effective amount of the formulation of any one of embodiments 1-46.    Embodiment 48. The method of embodiment 47, wherein the neurological    disease or disorder is schizophrenia.    Embodiment 49. The method of embodiment 47, wherein neurological    disease or disorder is the schizophrenia spectrum disorder,    schizophrenia negative symptoms, attenuated psychosis syndrome,    prodromal schizophrenia, delusional disorder, psychosis, attenuated    psychosis syndrome, psychotic disorder, delirium, Tourette's    syndrome, post-traumatic stress disorder, behavior disorder,    affective disorder, depression, bipolar disorder, major depressive    disorder, dysthymia, bipolar disorder, manic disorder, seasonal    affective disorder, obsessive-compulsive disorder, narcolepsy, REM    behavior disorder, substance abuse or dependency, Lesch-Nyhan    disease, Wilson's disease, autism, Alzheimer's disease agitation and    psychosis, or Huntington's chorea.    Embodiment 50. The method according to embodiment 49, wherein the    schizophrenia spectrum disorder is selected from schizophrenia,    attenuated psychosis syndrome, prodromal schizophrenia, schizoid    personality disorder, and schizotypal personality disorder.    Embodiment 51. The method of any one of embodiments 47-49, wherein    about 25 mg to about 100 mg per day of the salt of    (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine is    administered to the subject.    Embodiment 52. A method of preparing    (4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine,    comprising:-   (a) reacting 2-(thiophen-3-yl)ethan-1-ol with    N-methylaminoacetaldehyde dimethylacetal and triflic acid to provide    (4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine    triflate; and-   (b) reacting    (4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine    triflate with a base to provide    (4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine.    Embodiment 53. A method of preparing    (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine,    comprising:-   (a) reacting 2-(thiophen-3-yl)ethan-1-ol with    N-methylaminoacetaldehyde dimethylacetal and triflic acid to provide    (4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine    triflate;-   (b) reacting    (4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine    triflate with a base to provide    (4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine;-   (c) reacting    (4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine with    (R)-mandelic acid to provide    (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine    (R)-mandelate; and-   (d) reacting    (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine    (R)-mandelate with a base to provide    (S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanamine.

Various modifications of the invention, in addition to those describedherein, will be apparent to those skilled in the art from the foregoingdescription. Such modifications are also intended to fall within thescope of the appended claims. Each reference, including all patent,patent applications, and publications, cited in the present applicationis incorporated herein by reference in its entirety.

The invention claimed is:
 1. A compound which is crystalline(S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanaminehydrochloride characterized by a powder x-ray diffraction patterncomprising peaks, in terms of 2-theta, at 9.6±0.2°, 14.9±0.2°,20.5±0.2°, and 25.1±0.2°.
 2. The compound of claim 1, wherein thecrystalline(S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanaminehydrochloride is further characterized by the powder x-ray diffractionpattern further comprising a peak, in terms of 2-theta, at 20.2±0.2° and20.8±0.2°.
 3. The compound of claim 1 or 2, wherein the crystalline(S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanaminehydrochloride is further characterized by the powder x-ray diffractionpattern further comprising a peak, in terms of 2-theta, at two or moreof 17.9±0.2°, 24.8±0.2° and 27.1±0.2°.
 4. The compound of claim 1,wherein the crystalline(S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanaminehydrochloride is characterized by a powder x-ray diffraction pattern ofFIG. 2B.
 5. The compound of claim 1, wherein the crystalline(S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanaminehydrochloride has a differential scanning calorimetry thermogramcomprising a peak at 214±2° C.
 6. The compound of claim 1, wherein thecrystalline(S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanaminehydrochloride has a differential scanning calorimetry thermogram of FIG.3A.
 7. The compound of claim 1, wherein the crystalline(S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanaminehydrochloride is characterized by monoclinic space group P21.
 8. Thecompound of claim 1, wherein the crystalline(S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanaminehydrochloride has unit cell dimensions: α is about 9.2 Å, b is about11.2 Å, c is about 10.2 Å, α is about 90°, β is about 92°, and γ isabout 90°, wherein the term about means within 2% of each indicatedvalue.
 9. The compound of claim 1, wherein the crystalline(S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanaminehydrochloride has chiral purity greater than 90%(S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanaminehydrochloride.
 10. The compound of claim 1, wherein the crystalline(S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanaminehydrochloride has chiral purity greater than 95%(S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanaminehydrochloride.
 11. The compound of claim 1, wherein the crystalline(S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanaminehydrochloride has chemical purity greater than 95%(S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanaminehydrochloride.
 12. The compound of claim 1, wherein the crystalline(S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanaminehydrochloride has chemical purity greater than 99%(S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanaminehydrochloride.
 13. The compound of claim 1, wherein the crystalline(S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanaminehydrochloride has chemical purity of greater than 99.5%.
 14. Thecompound of claim 1, wherein the crystalline(S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanaminehydrochloride has polymorph purity of greater than 95%.
 15. The compoundof claim 1, wherein the crystalline(S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanaminehydrochloride has a Raman spectrum of FIG. 4A.
 16. The compound of claim1, wherein the crystalline(S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanaminehydrochloride has a THz Raman spectrum of FIG. 4D.
 17. The compound ofclaim 1, wherein the crystalline(S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanaminehydrochloride is substantially non-hygroscopic.
 18. A pharmaceuticalcomposition comprising the compound of any one of claims 1, 10, 12, or14 and one or more pharmaceutically acceptable excipients.
 19. Thepharmaceutical composition of claim 18 wherein the one or morepharmaceutically acceptable excipients are selected from the groupconsisting of fillers, disintegrants, and lubricants.
 20. Thepharmaceutical composition of claim 18 wherein the one or morepharmaceutically acceptable excipients are selected from the groupconsisting of mannitol, microcrystalline cellulose, sodium starchglycolate, and magnesium stearate.
 21. The pharmaceutical composition ofclaim 18 comprising: (a) 10 mg to 120 mg, on a free base basis, ofcrystalline(S)-(4,5-dihydro-7H-thieno[2,3-c]pyran-7-yl)-N-methylmethanaminehydrochloride; (b) mannitol; (c) microcrystalline cellulose; (d) sodiumstarch glycolate; and (e) magnesium stearate.